Pharmaceutical compositions and treatment methods

ABSTRACT

The invention provides compositions comprising formula 1 steroids, e.g., 16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate and one or more excipients, typically wherein the composition comprises less than about 3% water. The compositions are useful to make improved pharmaceutical formulations. The invention also provides methods of intermittent dosing of steroid compounds such as analogs of 16α-bromo-3β-hydroxy-5α-androstan-17-one and compositions useful in such dosing regimens. The invention further provides compositions and methods to inhibit pathogen (viral) replication, ameliorate symptoms associated with immune dysregulation and to modulate immune responses in a subject using certain steroids and steroid analogs. The invention also provides methods to make and use these immunomodulatory compositions and formulations.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of pending U.S. application Ser.No. 09/535,675, filed Mar. 23, 2000, which is a continuation-in-part ofabandoned U.S. provisional application Ser. No. 60/190,140, filed Mar.16, 2000, abandoned U.S. provisional application Ser. No. 60/164,048,filed Nov. 8, 1999, abandoned U.S. application Ser. No. 09/414,905,filed Oct. 8, 1999, abandoned U.S. provisional application Ser. No.60/140,028, filed Jun. 16, 1999, and abandoned U.S. provisionalapplication Ser. No. 60/126,056, filed Mar. 23, 1999, all of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] The invention relates to methods to make and use steroids, suchas 16α-bromo-3β-hydroxy-5α-androstane-17-one (16α-bromoepiandrosteroneor hereafter “BrEA”) and new analogs thereof. The steroids are usefulfor a number of therapeutic and non-therapeutic applications, includingtheir use as immune modulators. The present invention also relates tomethods to make the compounds, compositions and formulations.

[0003] BrEA and its preparation from the steroid compound3β-hydroxyandrost-5-en-17-one (dehydroepiandrosterone or “DHEA”) havebeen described (see, e.g., J. Org. Chem. 1962 27:2937-2938). Methods toprepare DHEA and other steroids and their biological properties havebeen described, see, e.g., U.S. Pat. Nos. 2,833,793, 2,911,418,3,148,198, 3,471,480, 3,976,691, 4,268,441, 4,427,649, 4,542,129,4,666,898, 4,956,355, 5,001,119, 5,043,165, 5,077,284, 5,028,631,5,110,810, 5,157,031, 5,162,198, 5,175,154, 5,277,907, 5,292,730,5,296,481, 5,372,996, 5,387,583, 5,407,684, 5,424,463, 5,461,042,5,478,566, 5,506,223, 5,518,725, 5,527,788, 5,527,789, 5,532,230,5,559,107, 5,562,910, 5,583,126, 5,585,371, 5,587,369, 5,591,736,5,593,981, 5,610,150, 5,635,496, 5,641,766, 5,641,768, 5,656,621,5,660,835, 5,686,438, 5,696,106, 5,700,793, 5,707,983, 5,709,878,5,710,143, 5,714,481, 5,728,688, 5,736,537, 5,744,462, 5,753,237,5,756,482, 5,776,921, 5,776,923, 5,780,460, 5,795,880, 5,798,347,5,798,348, 5,804,576, 5,807,848, 5,807,849, 5,811,418, 5,824,313,5,824,668, 5,824,671, 5,827,841, 5,837,269, 5,837,700, 5,843,932,5,846,963, 5,859,000, 5,872,114 and 5,872,147; German patent numbers2035738 and 2705917; PCT publication numbers WO 95/21617, WO 97/48367,WO 98/05338, WO 98/50040, WO 98/50041, WO 98/58650; European publicationnumber 0020029; Ben-David, et al., Proc. Soc. Expt. Biol. Med. 1967125:1136-1140, Coleman et al., Diabetes 1982 31:830, Oertel, et al., J.Steroid Biochem. 1972 3:493-496, Pashko, et al., Carcinogenesis 19812:717-721, Schwartz et al., Nutr. Cancer 1981 3:46-53; Dyner et al., J.Acquired Immune Deficiency Syndromes 1993 6:459-465; A. A. Afanasii andY. A. Titov, Total Steroid Synthesis, Plenum Press, New York, 1970, see,e.g., p 1-304.

[0004] The use DHEA and other steroids in various applications, e.g.,modulating immune responses have been described, e.g., U.S. Pat. Nos.5,869,090, 5,863,910, 5,856,340, 5,824,668, 5,804,576, 5,753,237,5,714,481, 5,709,878, 5,407,684, 5,206,008, 5,077,284, 4,978,532,4,898,694, 4,542,129, 3,711,606 and 3,710,795. U.S. Pat. No. 4,956,355and PCT publication number WO 97/48367, have described the use of BrEAand certain steroid compounds to treat certain virus or bacterialinfections, such as human immunodeficiency virus (“HIV”) infection.

[0005] Various biological effects and/or metabolic conversions ofsteroid compounds have been described, e.g., Batta et al., J. Biol.Chem. 1986 25:127-133, Belli et al., Liver 1991 11:162-169,Bhattacharjee et al., Anal. Biochem. 1992 201:233-236, Blake et al.,Int. J. Peptide Protein Res. 1982 20:97-101, 1986 25:127-133,Bonaventura, Am. J. Obstet. Gynecol. 1978 131:403-409, Bucala et al., J.Steroid Biochem. 1986 25:127-133, Carey et al., Biochem. 198120:3637-3648, Chen et al., Carcinogenesis 1999 20:249-254, Chen et al.,Carcinogenesis 1998 19:2187-2193, Chow et al., Antisense Res. Dev. 19944:81-86, Citro et al., Dis. Colon Rectum 1994 37(2 Suppl):S127-S132,Cleary, Proc. Soc. Exp. Biol. Med. 1991 196:8-16, Cleary, Int. J.Biochem. 1990 22:205-210, Crawford et al., Lab. Invest. 1994 71:42-51,Danenberg et al., Antimicrob. Agents Chemother. 1992 36:2275-2279,Dotzlaw et al., Cancer Res. 1999 59:529-532, Falany et al., J. SteroidBiochem. Mol. Biol. 1994 48:369-375, Faredin et al., J. InvestigativeDermatol. 1969 52:357-361, Galigniana et al., Mol. Pharmacol. 199955:317-323, Goto et al., J. Chromatogr. 1983 276:289-300, GrenotBiochem. 1992 31:7609-7621, Hofbauer et al., Life Sci. 1999 64:671-679,Huijghebaert et al., J. Lipid Res. 1986 27:742-752, Hurd et al.,Oncogene 1999 18:1067-1072, Iida et al., J. Lipid Res. 1995 36:628-638,Jellinck et al., Steroids 1967 10:329-346, Jonsson et al., J. Pediatr.Gastroenterol. Nutr. 1995 20:394-402, Kalimi et al, Mol. Cell. Biochem.1994 131:99-108, Kramer et al., J. Biol. Chem. 1994 269:10621-10627,LaRochelle et al., Steroids 1984 43: 209-217, Liao et al.,Carcinogenesis 1998 19:2173-2180, Lillienau et al., J. Clin. Invest.1992 89:420-431, Loria, Psychoneuroendocrinology 1997 22:S103-S108,Luscher et al Mol. Immunol. 1983 20:1099-1105, Manna et al., J. Biol.Chem. 1999 274:5909-5918, Marschall et al., J. Biol. Chem. 1989264:12989-12993, Medh et al., Cancer Res. 1998 15:3684-3693, Mohan etal., Steroids 1992 57:244-247, Munoz de Toro et al., J. Steroid Biochem.Mol. Biol. 1998 67:333-339, Padgett et al., J. Neuroimmunol. 1998 84:61,Padgett et al., Ann. N.Y. Acad. Sci. 1995 774:323, Padgett et al., J.Immunol. 1994 153:1544-1552, Pashko et al., Carcinogenesis 19845:463-466, Pashko et al., Carcinogenesis 1981 2:717, Petrylak et al., J.Clin. Oncology 1999 17:958-967, Podesta et al., Steroids 199661:622-626, Regelson et al., Ann. N.Y. Acad. Sci. 1994 719:564,Schmassmann et al., Gastroenterology 1993 104:1171-1181, Schmassmann etal., Hepatology 1990 11:989-996, Schreiber et al., Lancet 353:459-461,Schreiber, Neth. J. Med. 1998 53:S24-31, Schwartz et al., Cancer Res.1988 48:4817, Shahidi et al., Biochem. Biophys. Res. Commun. 1999254:559-565, Steer et al., Ann. Rheum. Dis. 1998 57:732-737, Suzuki etal., Steroids 1998 63:672-677, Suzuki et al., Steroids 1996 61:296-301,Swaan et al., Bioconjugate Chem. 1997 8:520-525, Tang et al, AnticancerDrug Res. 1998 13:815-824, Thomas et al., J. Steroid Biochem. 198625:103-108, Utsumi et al., Cancer Res. 1999 59:377-381, Vanden Heuvel,J. Nutr. 1999 129(2S Suppl.):575S-580S, Wang et al., Endocrinology 1998139:3903-3912, Wong et al., J. Biol. Chem. 1999 274:5443-5453, Xie etal., Endocrinology 1999 140:219-227, Yen et al., Lipids 1977 12:409-413,Zackheim et al., Arch. Dermatology 1998 134:949-954, Zhang et al.,Biochim. Biophys. Acta 1991 1096:179-186, Zhu et al., Carcinogenesis1988 19:2101-2106.

[0006] Compositions containing BrEA that were used to deliver thecompound to cells or cell extracts usually included a significant amountof water. Such compositions contained solvents such as dioxane ordimethylsulfoxide (“DMSO”), which contained water, or an aqueouscyclodextrin solutions to facilitate compound delivery to cells, see,e.g., J. Pharmacol Exp. Ther. 1998, 285:876-83, Cancer Res. 198646:3389-95, Carcinogenesis 1985 6:333-35, Carcinogenesis 1981 2:717-721,Carcinogenesis 1981 2:683-86. Such compositions are typically deliveredto animals by injection or to cells in tissue culture by addition tocell culture medium. European publication number EP 429 187 describesformulations that contain DHEA or BrEA and polyvinylpyrrolidone andcrosslinked polyvinylpyrrolidone. Some of these compositions may haveundesired or suboptimal properties. For example, solvents such asdioxane, DMSO or chloroform are generally not preferred or suitableparenteral excipients, particularly for human use. Formulations thatcontain BrEA or related steroids and that have improved properties,e.g., lower toxicity, improved chemical stability or desirablecharacteristics for large-scale synthesis are needed.

[0007] Mammalian immune responses to infections or other conditions areoften characterized by responses mediated by different effector cellpopulations. In some situations, helper T cells designated Th1 in themurine system, facilitate immune effector functions that are typicallydominated by cell-mediated responses. In other cases, helper T cellsdesignated Th2 cells facilitate immune effector functions that aretypically dominated by humoral responses. A vigorous Th1 response isusually needed to clear infections or to slow the progression of aninfection. When a subject's immune response is biased to, or dominatedby, a Th2-type response, the cytokines associated with the Th2 responsetend to suppress the immune system's capacity to mount a vigorous Th1response at the same time. The converse is also generally true. Whenmammalian immune responses begin to result in an increasing Th2response, the Th1 response to the same condition tends to weaken. WeakTh1 responses may be associated with progression of some infections orother conditions, see, e.g., M. Clerici and G. M. Shearer, Immunol.Today 14:107-111, 1993; M. Clerici and G. M. Shearer, Immunol. Today15:575-581, 1994. The invention provides compounds and compositionsuseful to enhance Th1 immune responses.

OBJECTS OF THE INVENTION

[0008] The invention compositions, formulations or methods accomplishone or more of the following objects.

[0009] One object of the invention is to provide new steroid compoundsor analogs that are suitable for therapeutic and other applications,such as immune modulators. Invention objects further include providingBrEA hemihydrate (BrEA₂.H₂O), compositions that comprise BrEAhemihydrate and methods to make and use it. Another object of theinvention is to provide liquid compositions and formulations thatcomprise a formula 1 compound(s), and that comprise about 3% (v/v) orless of water. Another object is to provide compositions one can use asintermediates to prepare human pharmaceutical and veterinaryformulations containing a formula 1 compound(s). Another object is toprovide intermittent dosing methods to deliver a formula 1 compound to asubject to enhance Th1 immune responses. Further objects are to providemethods to modulate innate immunity or to enhance Th1 immune responsesin a subject by administering to the subject a formula 1 compound(s)such as BrEA. Other objects are to provide methods to inhibit pathogen,e.g., viral, replication in a subject by administering to the subject aformula 1 compound(s) such as BrEA. Invention objects include providingformula 1 compounds or formulations useful to ameliorate one or moresymptoms of a pathological condition associated with immune suppressionor with deficient Th1 immune responses. Other objects are to providemethods to make and use compositions and formulations comprising aformula 1 compound(s).

BRIEF DESCRIPTION OF THE FIGURES

[0010]FIG. 1 is an FTIR (Fourier transform infrared) spectrum obtainedby USP method <197> of BrEA hemihydrate that was prepared byprecipitation of BrEA from ethanol and water.

[0011]FIG. 2 is a FTIR spectrum obtained by USP method <197> ofanhydrous BrEA that was prepared by precipitation of BrEA from anhydrousmethanol.

[0012]FIG. 3 shows a DSC endotherm of BrEA hemihydrate that was preparedby precipitation of BrEA from ethanol and water.

[0013]FIG. 4 shows a DSC endotherm of anhydrous BrEA that was preparedby precipitation of BrEA from anhydrous methanol.

[0014]FIG. 5 is an XRD (powder X-ray diffraction) spectrum of BrEAhemihydrate that was prepared by precipitation of BrEA from ethanol andwater.

[0015]FIG. 6 is a FTIR spectrum obtained by USP method <197> of BrEAhemihydrate that was prepared by precipitation of BrEA from acetone andwater.

SUMMARY OF THE INVENTION

[0016] In accordance with the objects, the invention provides BrEAhemihydrate

[0017] which is optionally characterized by reference to one or morephysical properties such as its melting point, infrared absorptionspectrum or its powder X-ray diffraction spectrum.

[0018] Related embodiments include BrEA hemihydrate and one or moreexcipients suitable for human pharmaceutical use or for veterinary use.Another related embodiment is a method to make BrEA hemihydratecomprising precipitating BrEA from a solution comprising ethanol andwater.

[0019] Invention embodiments include a composition comprising a compoundof formula 1

[0020] and one or more nonaqueous liquid excipients, wherein thecomposition comprises less than about 3% v/v water and wherein,

[0021] R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁰ independently are —H, —OR^(PR),—SR^(PR), —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, an ester, a thioester, aphosphoester, a phosphothioester, a phosphonoester, a phosphiniester, asulfite ester, a sulfate ester, an amide, an amino acid, a peptide, anether, a thioether, an acyl group, a thioacyl group, a carbonate, acarbamate, a thioacetal, a halogen, an optionally substituted alkylgroup, an optionally substituted alkenyl group, an optionallysubstituted alkynyl group, an optionally substituted aryl moiety, anoptionally substituted heteroaryl moiety, an optionally substitutedmonosaccharide, an optionally substituted oligosaccharide, a nucleoside,a nucleotide, an oligonucleotide, a polymer, or,

[0022] one more of R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R¹⁵, R¹⁷ and R¹⁸ are ═Oor ═S and the hydrogen atom that is bonded to the same carbon atom isabsent, or,

[0023] R³ and both R⁴ together comprise a structure of formula 2

[0024] R⁷ is —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —CHR¹⁰—CHR¹⁰—CHR¹⁰—,—CHR¹⁰—O—CHR¹⁰—, —CHR¹⁰—S—CHR¹⁰—, —CHR¹⁰—NR^(PR)—CHR¹⁰ —, —O—,—O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—;

[0025] R⁸ and R⁹ independently are —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —O—,—O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, or R⁸ or R⁹independently is absent, leaving a 5-membered ring;

[0026] R¹³ independently is C₁₋₆ alkyl;

[0027] R¹⁶ independently are —CH₂—, —O—, —S— or —NH—;

[0028] D is a heterocycle or a 4-, 5-, 6- or 7-membered ring thatcomprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms ofthe 4-, 5-, 6- or 7-membered ring are optionally independentlysubstituted with —O—, —S— or —NR^(PR)— or where 1, 2 or 3 hydrogen atomsof the heterocycle or where 1 or 2 hydrogen atoms of the 4-, 5-, 6- or7-membered ring are substituted with —OR^(PR), —SR^(PR), N(R^(PR))₂,—O—Si—(R¹³)₃, —CN, —NO₂, an ester, a thioester, a phosphoester, aphosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, asulfate ester, an amide, an amino acid, a peptide, an ether, athioether, an acyl group, a thioacyl group, a carbonate, a carbamate, athioacetal, a halogen, an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted aryl moiety, an optionally substitutedheteroaryl moiety, an optionally substituted monosaccharide, anoptionally substituted oligosaccharide, a nucleoside, a nucleotide, anoligonucleotide or a polymer, or,

[0029] one more of the ring carbons are substituted with ═O or ═S,

[0030] or D comprises two 5- or 6-membered rings, wherein the rings arefused or are linked by 1 or 2 bonds.

[0031] In other embodiments, the invention provides a compound offormula 1, wherein two or three of R⁷, R⁸ and R⁹ independently are not—CHR¹⁰—, wherein the compound is optionally present in a compositionthat comprises one or more excipients suitable for human pharmaceuticaluse or for veterinary use.

[0032] Invention embodiments also include a compound of formula 1

[0033] wherein,

[0034] R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁰ independently are —H, —OR^(PR),—SR^(PR), —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, an ester, a thioester, aphosphoester, a phosphothioester, a phosphonoester, a phosphiniester, asulfite ester, a sulfate ester, an amide, an amino acid, a peptide, anether, a thioether, an acyl group, a thioacyl group, a carbonate, acarbamate, a thioacetal, a halogen, an optionally substituted alkylgroup, an optionally substituted alkenyl group, an optionallysubstituted alkynyl group, an optionally substituted aryl moiety, anoptionally substituted heteroaryl moiety, an optionally substitutedmonosaccharide, an optionally substituted oligosaccharide, a nucleoside,a nucleotide, an oligonucleotide, a polymer, or,

[0035] one, two or more of R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁰ independentlyare ═O or ═S and the hydrogen atom that is bonded to the same carbonatom is absent, or,

[0036] R³ and R⁴ together comprise a structure of formula 2

[0037] R⁷ is —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —CHR¹⁰—CHR¹⁰—CHR¹⁰—,—CHR¹⁰—O—CHR¹⁰—, —CHR¹⁰—S—CHR¹⁰—, —CHR¹⁰NR^(PR)—CHR¹⁰—, —O—, —O—CHR¹⁰—,—S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—;

[0038] R⁸ and R⁹ independently are —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —O—,—O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, or R⁸ or R⁹independently is absent, leaving a 5-membered ring;

[0039] R¹³ independently is C₁-6 alkyl;

[0040] D is a heterocycle or a 4-, 5-, 6- or 7-membered ring thatcomprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms ofthe 4-, 5-, 6- or 7-membered ring are optionally independentlysubstituted with —O—, —S— or —NR^(PR)— or where 1, 2 or 3 hydrogen atomsof the heterocycle or where 1 or 2 hydrogen atoms of the 4-, 5-, 6- or7-membered ring are substituted with —OR^(PR), —SR^(PR), —N(R^(PR))₂,—O—Si—(R¹³)₃, —CN, —NO₂, an ester, a thioester, a phosphoester, aphosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, asulfate ester, an amide, an amino acid, a peptide, an ether, athioether, an acyl group, a thioacyl group, a carbonate, a carbamate, athioacetal, a halogen, an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted aryl moiety, an optionally substitutedheteroaryl moiety, an optionally substituted monosaccharide, anoptionally substituted oligosaccharide, a nucleoside, a nucleotide, anoligonucleotide or a polymer, or,

[0041] one or more of the ring carbons are substituted with ═O or ═S,

[0042] or D comprises two 5- or 6-membered rings, wherein the rings arefused or are linked by 1 or 2 bonds, wherein one, two or three of R⁷, R⁸and R⁹ are not —CHR¹⁰—.

[0043] Other embodiments include a method to enhance the expression ofone or more cytokines or interleukins that facilitate Th1 immuneresponses in a subject or to reduce the expression of one or morecytokines or interleukins that facilitate Th2 immune response in asubject comprising administering to the subject an effective amount ofthe composition of claim 32, whereby the subject's Th1 immune responseis enhanced ot the subject's undesired Th2 immune response is reduced.

[0044] Embodiments include liquid formulations that comprise a formula 1compound, one or more excipients and less than about 3% water, whereinthe formulation is optionally disposed in containers that exclude water.

[0045] Another embodiment is a method comprising intermittentadministration of a formula 1 compound, to a subject having apathological condition, such as a viral or parasite infection.

[0046] A further embodiment is a method to modulate a subject's innateimmunity, Th1 immune responses or Th2 immune responses comprisingadministering a formula 1 compound to a subject.

[0047] Other embodiments are as described in the specification includingthe appended numbered embodiments and the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0048] Definitions.

[0049] As used herein and unless otherwise stated or implied by context,the following terms have the meanings defined here.

[0050] An “invention formulation” or “formulation” means an inventioncomposition that one can administer parenterally to a human or animalwithout further manipulations that change the ingredients or theingredient proportions that are present. Formulations are suitable forhuman or veterinary applications.

[0051] An “invention composition” is a composition that is anintermediate one can use to make the invention formulations, i.e., achange(s) in an ingredient(s) or its amount(s) is needed to make aformulation. Thus, invention compositions include compositions wherefurther processing is required before it is a formulation, e.g., mixingor addition of a desired amount of an ingredient.

[0052] An “excipient” means a component or an ingredient that isacceptable in the sense of being compatible with the other ingredientsof invention compositions or formulations and not overly deleterious tothe patient or animal to which the formulation is to be administered. Asused here, “excipients” include liquids, such as benzyl benzoate,cottonseed oil, N,N-dimethylacetamide, a C₂₋₁₂ alcohol (e.g., ethanol),glycerol, peanut oil, a polyethylene glycol (“PEG”), vitamin E,poppyseed oil, propylene glycol, safflower oil, sesame oil, soybean oiland vegetable oil. Excipients, as used herein will optionally excludechloroform, dioxane, vegetable oil, DMSO or any combination of these.Excipients comprise one or more components typically used in thepharmaceutical formulation arts, e.g., fillers, binders, disintegrantsand lubricants.

[0053] A “subject” means a human or animal. Usually the animal is avertebrate such as a primate, rodent, domestic animal or game animal.Primates include chimpanzees, cynomologous monkeys, spider monkeys, andmacaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets,rabbits and hamsters. Domestic and game animals include cows, horses,pigs, deer, bison, buffalo, felines, e.g., domestic cat, canines, e.g.,dog, avians, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfishand salmon. Subject includes any subset of the foregoing, e.g., all ofthe above, but excluding one or more groups or species such as humans,primates or rodents.

[0054] Expressions that refer to “a formula 1 compound(s)” or “a formula1 compound” mean invention compositions or formulations where one ormore than one formula 1 compound is present, typically 1, 2, 3 or 4,usually 1.

[0055] “Alkyl” as used here means linked normal, secondary, tertiary orcyclic carbon atoms, i.e., linear, branched or cyclic. The number ofcarbon atoms in an alkyl group or moiety is 1 to about 20, unlessotherwise specified, e.g., C₁₋₈ alkyl means an alkyl moiety containing1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Examples include methyl, ethyl,1-propyl (n-propyl), 2-propyl (i-propyl, —CH(CH₃)₂), 1-butyl (n-butyl),2-methyl-1-propyl (i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-butyl,—CH(CH₃)CH₂CH₃ ), 2-methyl-2-propyl (t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂),2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂),3-methyl-1 -butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl, 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (-CH (CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH (CH₃)C(CH₃)₃),cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0056] “Alkenyl” means linked normal, secondary, tertiary or cycliccarbon atoms where one or more double bonds (e.g., —CH═CH—) are present,typically 1, 2 or 3, usually 1 or 2. The number of carbon atoms in analkenyl group or moiety is 2 to about 20, unless otherwise specified,e.g., C₁₋₈ alkenyl means an alkenyl moiety containing 1, 2, 3, 4, 5, 6,7 or 8 carbon atoms.

[0057] “Alkynyl” means linked normal, secondary, tertiary or cycliccarbon atoms where one or more triple bonds (—C—C—) are present,typically 1, 2 or 3, usually 1. The number of carbon atoms in an alkynylgroup or moiety is 2 to about 20, unless otherwise specified, e.g., C18alkynyl means an alkynyl moiety containing 1, 2, 3, 4, 5, 6, 7 or 8carbon atoms.

[0058] “Aryl” means phenyl or naphthyl.

[0059] “Substituted alkyl”, “substituted alkenyl” and “substitutedalkynyl” mean an alkyl, alkenyl or alkynyl group that has asubstituent(s) linked to a carbon atom or substituent(s) that interrupta carbon atom chain. Substituents include ethers (—O—), ketones(—C(O)—), —OR^(PR), —C(O)OR^(PR), —C(O)O—, —C(S)OR^(PR), —C(S)O—,—OC(O)—, —C(O)H, —OCH₂—, —OCH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —NR^(PR)—,—N(R^(PR))₂, —NHR^(PR), —NHC(O)—, —CH₂—NR^(PR)—, —CH₂—NHR^(PR),—CH₂—NHC(O)—, —C(O)NH—, —C(O)NHR^(PR), —OC(O)NR^(PR)—, —OC(O)NHR^(PR),—NR^(PR)C(O)NR^(PR)—, —NR^(PR)C(O)NHR^(PR), —NR^(PR)CH₂—,—NR^(PR)CH₂CH₂—, —S—, —SR^(PR), —S(O)—, —S(O)(O)—, —S(O)OR^(PR), —S(O)H,—CN, —NO₂, halogen, and combinations of these moieties where R^(PR)independently is hydrogen, a protecting group or both R^(PR) togetherare a protecting group. Substituents are independently chosen when morethan one is present. Alkenyl and alkynyl groups that comprise asubstituent(s), are typically substituted at a carbon that is one ormore methylene moiety removed from the double bond, e.g., separated atleast by one, two or more —CH₂— moieties.

[0060] Heterocycle.

[0061] “Heterocycle” or “heterocyclic” includes by way of example andnot limitation the heterocycles described in Paquette, Leo A.;“Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York,1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry ofHeterocyclic Compounds, A series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. 1960,-82:5566.

[0062] Examples of heterocycles include by way of example and notlimitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidizedtetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl,6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2dithiazinyl, thienyl, thianthrenyl,pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,and isatinoyl.

[0063] By way of example and not limitation, carbon bonded heterocyclesare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

[0064] By way of example and not limitation, nitrogen bondedheterocycles are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline. Typically,nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl,1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0065] “Heteroaryl” means an aromatic ring or two or more fused ringsthat contain one or more aromatic rings where the ring or fused ringscomprise 1, 2, 3 or more heteroatoms, usually oxygen (—O—), nitrogen(—NX—) or sulfur (—S—) where X is —H, a protecting group or C₁₋₆ alkyl,usually —H. Examples are as described for heterocycle.

[0066] “Alcohol” as used herein, usually in the context of excipients,means an alcohol that comprises a C₂₋₁₂ alkyl moiety substituted at ahydrogen atom with one hydroxyl group. Alcohols include ethanol,n-propanol, i-propanol, n-butanol, i-butanol, s-butanol, t-butanol,n-pentanol, i-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octanol,n-nonanol and n-decanol. The carbon atoms in alcohols can be straight,branched or cyclic. Alcohol includes any subset of the foregoing, e.g.,C₂₋₄ alcohols (alcohols having 2, 3 or 4 carbon atoms).

[0067] “Halogen” means fluorine, chlorine, bromine or iodine.

[0068] “Protecting group” means a moiety that prevents the atom to whichit is linked from participating in unwanted reactions. For example, for—OR^(PR), R^(PR) may be hydrogen or a protecting group for the oxygenatom found in a hydroxyl, while for —C(O)— OR^(PR), R^(PR) may behydrogen or a carboxyl protecting group, for —SR^(PR), R^(PR) may behydrogen or a protecting group for sulfur in thiols for instance, andfor —NHR^(PR) or —N(R^(PR))₂—, R^(PR) may be hydrogen or a nitrogen atomprotecting group for primary or secondary amines. Hydroxyl, amine andother reactive groups are found in formula 1 compounds at, e.g., R¹ orR². These groups may require protection against reactions taking placeelsewhere in the molecule. The protecting groups for oxygen, sulfur ornitrogen atoms are usually used to prevent unwanted reactions withelectrophilic compounds, such as acylating used, e.g., in steroidchemistry.

[0069] “Ester” means a moiety that comprises a —C(O)—O— structure.Typically, esters as used here comprise an organic moiety containingabout 1-50 carbon atoms (e.g., about 2-20 carbon atoms) and 0 to about10 independently selected heteroatoms (e.g., O, S, N, P, Si), where theorganic moiety is bonded to a formula 1 steroid nucleus at, e.g., R¹ orR² through the —C(O)—O— structure, e.g., organic moiety-C(O)—O-steroidor organic moiety-O—C(O)-steroid. The organic moiety usually comprisesone or more of any of the organic groups described above, e.g., C₁₋₂₀alkyl moieties, C₂₋₂₀ alkenyl moieties, C₂₋₂₀ alkynyl moieties, arylmoieties, C₂₋₉ heterocycles or substituted derivatives of any of these,e.g., comprising 1, 2, 3, 4 or more substituents, where each substituentis independently chosen. Typical substitutions for hydrogen or carbonatoms in these organic groups include 1, 2, 3, 4 or more, usually 1, 2,or 3 —O—, —S—, —NR^(PR)— (including —NH—), —C(O)—, ═O, ═S, —N(R^(PR))₂(including —NH₂), —C(O)OR^(PR) (including —C(O)OH), —OC(O)R^(PR)(including —O—C(O)—H), —OR^(PR) (including —OH), —SR^(PR) (including—SH), —NO₂, —CN, —NHC(O)—, —C(O)NH—, —OC(O)—, —C(O)O—, —O-A8, —S-A8,—C(O)-A8, —OC(O)-A8, —C(O)O-A8, ═N—, —N═, ═N—OH, —OPO₃(R^(PR))₂, —OSO₃H₂or halogen moieties or atoms, where each R^(PR) is —H, an independentlyselected protecting group or both R^(PR) together comprise a protectinggroup, and A8 is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkyl-aryl(e.g., benzyl), aryl (e.g. phenyl) or C₀₋₄ alkyl-C₂₋₉ heterocycle.Substitutions are independently chosen. The organic moiety includescompounds defined by the R₄ variable. The organic moieties excludeobviously unstable moieties, e.g., —O—O—, except where such unstablemoieties are transient species that one can use to make a compound withsufficient chemical stability for one or more of the uses describedherein. The substitutions listed above are typically substituents thatone can use to replace one or more carbon atoms, e.g., —O— or —C(O)—, orone or more hydrogen atom, e.g., halogen, —NH₂ or —OH.

[0070] “Thioester” means a moiety that comprises a —C(S)—O— structure.Typically, thioesters as used here comprise an organic moiety containingabout 1-50 carbon atoms (e.g., about 2-20 carbon atoms) and 0 to about10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety isbonded to a formula 1 steroid nucleus at R² through the —C(S)—O—structure, e.g., organic moiety-C(S)—O-steroid or organicmoiety-O—C(S)-steroid. The organic moiety is as described above foresters.

[0071] “Thioacetal” means a moiety that comprises a —C(O)—S— structure.Typically, thioacetals as used here comprise an organic moietycontaining about 1-50 carbon atoms (e.g., about 2-20 carbon atoms) and 0to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moietyis bonded to a formula 1 steroid nucleus at R² through the —C(O)—S—structure, e.g., organic moiety-C(O)—S-steroid or organicmoiety-S—C(O)-steroid. The organic moiety is as described above foresters.

[0072] “Phosphoester” or “phosphate ester” means a moiety that comprisesa —O—P(ORPR)(O)—O— structure where RPR is hydrogen (—H), a protectinggroup or an organic moiety as described for esters. Typically,phosphoesters as used here comprise a hydrogen atom, a protecting groupor an organic moiety containing about 1-50 carbon atoms and 0 to about10 heteroatoms (e.g., O, S, N, P, Si) linked to a formula 1 steroidnucleus at R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through the —O—P(O)(O)—O—structure, e.g., organic moiety-O—P(O)(OH)—O-steroid. The organic moietyis as described above for esters.

[0073] “Phosphothioester” means a moiety that comprises a—O—P(SRPR)(O)—O— structure where R^(PR) is —H, a protecting group or anorganic moiety as described for esters. Typically, phosphothioesters asused here comprise a hydrogen atom, a protecting group or an organicmoiety containing about 1-50 carbon atoms and 0 to about 10 heteroatoms(e.g., O, S, N, P, Si) linked to a formula 1 steroid nucleus at R¹-R⁶,R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through the —O—P(O)(O)—O— structure, e.g., organicmoiety-O—P(O)(SH)—O-steroid. The organic moiety is as described abovefor esters.

[0074] “Phosphonoester” means a moiety that comprises a—P(OR^(PR))(O)—O— structure where R^(PR) is —H, a protecting group or anorganic moiety as described for esters. Typically, phosphonoesters asused here comprise a hydrogen atom, a protecting group or an organicmoiety containing about 1-50 carbon atoms and 0 to about 10 heteroatoms(e.g., O, S, N, P, Si) linked to a formula 1 steroid nucleus at R¹-R⁶,R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through the —P(OR^(PR))(O)—O— structure, i.e.,organic moiety-P(ORPR)(O)—O-steroid or steroid-P(OR^(PR))(O)—O-organicmoiety. The organic moiety is as described above for esters.

[0075] “Phosphiniester” means a moiety that comprises a —P(ORPR)—O—structure where RPR is —H, a protecting group or an organic moiety asdescribed for esters. Typically, phosphiniesters as used here comprise ahydrogen atom, a protecting group or an organic moiety containing about1-50 carbon atoms and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si)linked to a formula 1 steroid nucleus at R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹through the —P(ORPR)—O— structure, i.e., organicmoiety-P(OR^(PR))—O—-steroid or steroid-P(OR^(PR))—O-organic moiety. Theorganic moiety is as described above for esters.

[0076] “Sulfate ester” means a moiety that comprises a —P—S(O)(O)—O—structure. Typically, sulfate esters as used here comprise a hydrogenatom, a protecting group or an organic moiety containing about 1-50carbon atoms and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si) linkedto a formula 1 steroid nucleus at R¹-R⁶, R¹⁰, R ⁵, R¹⁷ or R¹⁸ throughthe —O—S(O)(O)—O— structure, e.g., organic moiety-O—S(O)(O)—O-steroid.The organic moiety is as described above for esters.

[0077] “Sulfite ester” means a moiety that comprises a —O—S(O)—O—structure. Typically, sulfite esters as used here comprise an organicmoiety containing about 1-50 carbon atoms and 0 to about 10 heteroatoms(e.g., O, S, N, P, Si) linked to a formula 1 steroid nucleus at R¹-R⁶,R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through the —O—S(O)—O— structure, e.g., organicmoiety-O—S(O)—O-steroid. The organic moiety is as described above foresters.

[0078] “Thioacetal” means a moiety that comprises a —S—C(O)— structure.Typically, thioacetal groups as used here comprise an organic moietycontaining about 1-50 carbon atoms and 0 to about 10 heteroatoms (e.g.,O, S, N, P, Si) linked to a formula 1 steroid nucleus at R¹-R⁶, R¹⁰,R¹⁵, R¹⁷ or R¹⁸ through the —S—C(O)— structure, e.g., organicmoiety-S—C(O)-steroid or steroid-S—C(O)-organic moiety. The organicmoiety is as described above for esters.

[0079] “Amide” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —C(O)—NR^(PR)-moieties, usually 1 or 2,where R^(PR) is —H or a protecting group, R^(PR) is usually H. In someembodiments, the —C(O)NR^(PR)-group is linked to the steroid nucleus atR¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸, i.e., organic moiety-C(O)NR^(PR)-steroid orsteroid-C(O)NR^(PR)-organic moiety.

[0080] “Ether” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —O— moieties, usually 1 or 2. In someembodiments, the —O— group is linked to the steroid nucleus at R¹-R⁶,R¹⁰, R¹⁵, R¹⁷ or R¹⁸, e.g., organic moiety-O-steroid.

[0081] “Thioether” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —S— moieties, usually 1 or 2. In someembodiments, the —S— group is linked to the steroid nucleus at R¹-R⁶,R¹⁰, R¹⁵, R¹⁷ or R¹⁸, e.g., organic moiety-S-steroid.

[0082] “Acyl group” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —C(O)— groups. In some embodiments, the—C(O)— group is linked to the steroid nucleus at R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ orR¹⁸, e.g., organic moiety-C(O)-steroid.

[0083] “Thioacyl” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —C(S)— groups. In some embodiments, the—C(S)— group is linked to the steroid nucleus at R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ orR¹⁸, e.g., organic moiety-C(S)-steroid.

[0084] “Carbonate” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —O—C(O)—O— structures. Typically, carbonategroups as used here comprise an organic moiety containing about 1-50carbon atoms and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si) linkedto a formula 1 steroid nucleus at R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ throughthe —O—C(O)—O— structure, e.g., organic moiety-O—C(O)—O-steroid.

[0085] “Carbamate” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —O—C(O)NR^(PR)-structures where R^(PR) is—H, a protecting group or an organic moiety as described for ester.Typically, carbamate groups as used here comprise an organic moietycontaining about 1-50 carbon atoms and 0 to about 10 heteroatoms (e.g.,O, S, N, P, Si) linked to a formula 1 steroid nucleus at R¹-R⁶, R¹⁰,R¹⁵, R¹⁷ or R¹⁸ through the —O—C(O)—NR^(PR)-structure, e.g., organicmoiety-O—C(O)—NR^(PR)-steroid or steroid-O—C(O)—NR^(PR)-organic moiety.

[0086] As used herein, “monosaccharide” means a polyhydroxy aldehyde orketone having the empirical formula (CH₂O)_(n) where n is 3, 4, 5, 6 or7. Monosaccharide includes open chain and closed chain forms, but willusually be closed chain forms. Monosaccharide includes hexofuranose andpentofuranose sugars such as 2′-deoxyribose, ribose, arabinose, xylose,their 2′-deoxy and 3′-deoxy derivatives and their 2′,3′-dideoxyderivatives. Monosaccharide also includes the 2′,3′ dideoxydidehydroderivative of ribose. Monosaccharides include the D-, L- and DL-isomersof glucose, fructose, mannose, idose, galactose, allose, gulose,altrose, talose, fucose, erythrose, threose, lyxose, erythrulose,ribulose, xylulose, ribose, arabinose, xylose, psicose, sorbose,tagatose, glyceraldehyde, dihydroxyacetone and their monodeoxyderivatives such as rhamnose. Monosaccharides are optionally protectedor partially protected.

[0087] Optionally substituted alkyl group, optionally substitutedalkenyl group, optionally substituted alkynyl group, optionallysubstituted aryl moiety and optionally substituted heterocycle meansubstitutions that include C₁₋₂₀ alkyl moieties, C₂₋₂₀ alkenyl moieties,C₂₋₂₀ alkynyl moieties, aryl moieties, C₂₋₉ heterocycles or substitutedderivatives of any of these. Typical substitutions for these organicgroups include 1, 2, 3, 4 or more, usually 1 or 2, —O—, —S—, —NR^(PR)—,—C(O)—, —N(R^(PR))₂, —C(O)OR^(PR), —OC(O)R^(PR), —OR^(PR), —SR^(PR),—NO₂, —CN, —NHC(O)—, —C(O)NH—, —OC(O)—, —C(O)O—, —O-A8, —S-A8, —C(O)-A8,—OC(O)-A8, —C(O)O-A8, ═N—, —N═, —OPO₂R^(PR), —OSO₃H or halogen moietiesor atoms, where R^(PR) independently is —H, a protecting group or bothR^(PR) together are a protecting group and A8 is C₁₋₈ alkyl, C₁₋₈alkenyl, C₁₋₈ alkynyl, C₁₋₄ alkyl-aryl (e.g., benzyl), aryl (e.g.phenyl) or C₁₋₄ alkyl-C₁₋₅ heterocycle. Substitutions are independentlychosen. The organic moieties as described here, and for other any othermoieties described herein, exclude obviously unstable moieties, e.g.,—O—O—, except where such unstable moieties are transient species thatone can use to make a compound with sufficient chemical stability forthe one or more of the uses described herein.

[0088] Optionally substituted “monosaccharide” comprise any C3-C7 sugar,D-, L- or DL-configurations, e.g., erythrose, glycerol, ribose,deoxyribose, arabinose, glucose, mannose, galactose, fucose, mannose,glucosamine, N-acetylneuraminic acid, N-acetylglucosamine,N-acetylgalactosamine that is optionally substituted at one or morehydroxyl groups. Suitable substitutions include hydrogen, protectedhydroxyl, carboxyl, azido, cyano, —O-C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —O—C₂₋₆alkenyl, —S—C₂₋₆ alkenyl, optionally protected amine, optionallyprotected carboxyl, halogen, thiol or protected thiol. The linkagebetween the monosaccharide the steroid is α or β.

[0089] Optionally substituted “oligosaccharide” comprises two, three,four or more of any C3-C7 sugars that are covalently linked to eachother. The linked sugars may have D-, L- or DL-configurations. Suitablesugars and substitutions are as described for monosaccharides. Thelinkage between the oligosaccharide and the steroid is α or β, as arethe linkages between the monosaccharides that comprise theoligosaccharide.

[0090] Nucleoside includes 3TC, AZT, D4T, ddl, ddC, G, A, U, C, T, dG,dA, dT and dC.

[0091] Polymer includes biocompatible organic polymers, e.g., PEGs andpolyhydroxyalkyl polymers.

[0092] PEG means an ethylene glycol polymer that contains about 20 toabout 2000000 linked monomers, typically about 50-1000 linked monomers,usually about 100-300. Polyethylene glycols include PEGs containingvarious numbers of linked monomers, e.g., PEG20, PEG30, PEG40, PEG60,PEG80, PEG100, PEG115, PEG 200, PEG 300, PEG400, PEG500, PEG600, PEG1000, PEG1500, PEG2000, PEG 3350, PEG4000, PEG4600, PEG5000, PEG6000,PEG8000, PEG1 000, PEG12000, PEG2000000 and any mixtures thereof.

[0093] Amino Acid.

[0094] “Amino acid” means an amino acid moiety that comprises anynaturally-occurring or synthetic amino acid residue, i.e., any moietycomprising at least one carboxyl and at least one amino residue directlylinked by one, two three or more carbon atoms, typically one (α) carbonatom. The nature and identity of the intervening structure locatedbetween the carboxyl and amino groups can have a variety of structuresincluding those described herein. Typically, amino acids linked to thesteroid through the amine group have sufficient conformation and lengthto be capable of autocatalytic hydrolysis of the amino acid-steroid bondand release of the steroid. This can occur when the free carboxyl isgenerated in vivo by deesterification, deamidation or peptidolyticcleavage of the precursor containing a linkage between the amino acid'samine group and the steroid. Hydrolysis of the bond between an aminoacid's carboxyl or amino group and the steroid can also occur bychemical or enzymatic activity, e.g., esterase cleavage or non-enzymatichydrolysis.

[0095] In general, the amino acids corresponding to the residuesemployed in the invention compounds are naturally occurring and have nosignificant pharmacological activity per se. However, optimalpharmacokinetic activity, (substantially complete hydrolysis uponhydrolysis of the distal amide or ester bond) may be achieved by usingnon-naturally occurring amino acid residues. The intervening structuremay be as simple as methylene when the amino acid residue is glycyl, orsubstituted methylene for other α amino acids. The structure ordinarilycontains up to about 5 carbon or heteroatoms in the direct linkagebetween the amino acid's carboxyl carbon and the amine nitrogen. Thus,amino acids can comprise intervening ethylene, propylene, butylene, orpentylene groups or their substituted analogs, such as for example,oxyesters or ethers in which oxygen replaces carbon and, as appropriate,hydrogen. An example of such an intervening structure would be—CH—O—C(R²²)(R²³)—, where R²² and R²³ are independently selectedhydrogen or organic moieties as described above for esters. In someembodiments one of R²² and R²³ is hydrogen and the other is a C2-20organic moiety. Typically the organic moieties contain about 1-20 carbonatoms and 0, 1, 2, 3, 4 or 5 independently selected heteroatoms, whichare typically selected from oxygen, nitrogen, sulfur and phosphorus. Ingeneral, fewer intervening atoms are used when more rapid hydrolysis isdesired, although larger structures are suitable if, e.g., they possesssufficient flexibility or have conformations to allow positioning of thecarboxyl group in proximity to the amino acid-steroid bond.

[0096] Ordinarily, R²² is —H, methyl or hydroxymethyl, usually —H, andR²³ is a side chain or group of a naturally occurring amino acid. Aminoacid side chains include analogs where the side chain is a C₁₋₁₅ homologof the corresponding natural compound, e.g., methylene, ethylene,propylene, butylene or a substituted derivative thereof, e.g., an alkyl,ether or alkoxy (e.g., methoxy, ethoxy, propoxy) substituted derivative.In general, for carboxyl-containing side chains, if the C atom of theside chain carboxyl is linked by 5 or less atoms to the N then thecarboxyl optionally will be blocked, e.g. by esterification or amidationwherein the ester or amide bonds are hydrolyzable in vivo. R²² also istaken together with R³⁰ to form a proline residue (—CH₂—)₃. Thus, R²³ isgenerally a side group such as —H, —CH₃, —CH(CH₃)₂, —CH₂—CH(CH₃)₂,—CHCH₃—CH₂—CH₃, —CH₂—C₆H₅, —CH₂CH₂—S—CH₃, —CH₂OH, —CH(OH)—CH₃, —CH₂—SH,—CH₂—C₆H₄OH, —CH₂—CO—NH₂, —CH₂—CH₂—CO—NH₂, —CH₂—COOH, —CH₂—CH₂—COOH,—(CH₂)₄—NH₂ and —(CH₂)₃—NH—C(NH₂)—NH₂. R²³ also includes1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl,indol-3-yl, methoxyphenyl and ethoxyphenyl. The optimal R³⁰ group isreadily selected using routine assays.

[0097] In general, the amino acid residue has the structure shown in theformulas below. Ordinarily, n is 1 or 2, R²² is —H and R²³ is a moietycontaining one or more of the following groups: amino, carboxyl, amide,carboxyl ester, hydroxyl, C₆-C₇ aryl, ether (—O—), thioether (—S—), n-,s- or t-alkyl (C₁-C₆), guanidinyl, imidazolyl, indolyl, sulfhydryl,sulfoxide, and phosphoryl. The R²² and R²³ substituents can have a widevariety of structures including those disclosed herein, e.g., esters,ethers or carbonates.

[0098] When the amino acid residues contain one or more chiral centers,any of the D, L, meso, threo or erythro (as appropriate) racemates ormixtures thereof, fall within the scope of this invention. In general,if it is desired to rely on non-enzymatic means of hydrolysis, D isomersshould be used. On the other hand, L isomers may be more versatile sincethey can be susceptible to both non-enzymatic as well as potentialtargeted enzymatic hydrolysis, and are more efficiently transported byamino acid or dipeptidyl transport systems in the gastrointestinaltract.

[0099] Examples of suitable amino acid residues include the following:Glycyl; aminopolycarboxylic acids, e.g., aspartic acid,β-hydroxyaspartic acid, glutamic acid, β-hydroxyglutamic acid,β-methylaspartic acid, β-methylglutamic acid, β,β-dimethylaspartic acid,γ-hydroxyglutamic acid, β,γ-dihydroxyglutamic acid, β-phenylglutamicacid, γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid,2-aminosuberic acid and 2-aminosebacic acid residues; amino acid amidessuch as glutaminyl and asparaginyl; polyamino- orpolybasic-monocarboxylic acids such as arginine, lysine, β-aminoalanine,γ-aminobutyrine, ornithine, citruline, homoarginine, homocitrulline,5-hydroxy-2,6-diaminohexanoic acid (commonly, hydroxylysine, includingallohydroxylysine) and diaminobutyric acid residues; other basic aminoacid residues such as histidinyl; diaminodicarboxylic acids such asα,α′-diaminosuccinic acid, α,α′-diaminoglutaric acid, α,α′-diaminoadipicacid, α,α′-diaminopimelic acid, α,α′-diamino-β-hydroxypimelic acid,α,α′-diaminosuberic acid, α,α′-diaminoazelaic acid, andα,α′-diaminosebacic acid residues; imino acids such as proline, 4- or3-hydroxy-2-pyrrolidinecarboxylic acid (commonly, hydroxyproline,including allohydroxyproline), γ-methylproline, pipecolic acid,5-hydroxypipecolic acid, —N([CH₂]_(n)COOR^(PR))₂, wherein n is 1, 2, 3,4, 5 or 6 and RPR is -H or a protecting group, andazetidine-2-carboxylic acid residues; a mono- or di-alkyl (typicallyC₁-C₈ branched or normal) amino acid such as alanine, valine, leucine,allylglycine, butyrine, norvaline, norleucine, heptyline,α-methylserine, α-amino-α-methyl-γ-hydroxyvaleric acid,α-amino-α-methyl-δ-hydroxyvaleric acid,α-amino-α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamicacid, α-aminoisobutyric acid, α-aminodiethylacetic acid,α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid,α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid,α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid,α-aminodiisoamyacetic acid, a-methylaspartic acid, α-methylglutamicacid, 1-aminocyclopropane-1-carboxylic acid; isoleucine, alloisoleucine,tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionicacid residues; β-phenylserinyl; aliphatic α-amino-β-hydroxy acids suchas serine, β-hydroxyleucine, β-hydroxynorleucine, β-hydroxynorvaline,and α-amino-β-hydroxystearic acid residues; α-Amino, α-, γ-, δ- orε-hydroxy acids such as homoserine, γ-hydroxynorvaline,δ-hydroxynorvaline and epsilon-hydroxynorleucine residues; canavinyl andcanalinyl; γ-hydroxyornithinyl; 2-Hexosaminic acids such asD-glucosaminic acid or D-galactosaminic acid residues; α-amino-β-thiolssuch as penicillamine, β-thiolnorvaline or β-thiolbutyrine residues;other sulfur containing amino acid residues including cysteine;homocystine; β-phenylmethionine; methionine; S-allyl-L-cysteinesulfoxide; 2-thiolhistidine; cystathionine; and thiol ethers of cysteineor homocysteine; phenylalanine, tryptophan and ring-substituted a aminoacids such as the phenyl- or cyclohexylamino acids α-aminophenylaceticacid, α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionicacid; phenylalanine analogues and derivatives comprising aryl, loweralkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur orhalo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-,p-chloro-, 3,4-dicloro, o-, m- or p-methyl-, 2,4,6-trimethyl-,2-ethoxy-5-nitro, 2-hydroxy-5-nitro and p-nitro-phenylalanine); furyl-,thienyl-, pyridyl-, pyrimidinyl-, purine or naphthylalanines; andtryptophan analogues and derivatives including kynurenine,3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophanresidues; α-amino substituted amino acid residues including sarcosine(N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine,N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline andN-benzylvaline; and α-Hydroxy and substituted α-hydroxy amino acidresidues including serine, threonine, allothreonine, phosphoserine andphosphothreonine residues.

[0100] Any one of the foregoing or other known amino acids are suitablyemployed in this invention. Typically amino acids are capable ofautocatalytically hydrolyzing the amino acid-steroid bond. Thus, theytypically contain, or upon being hydrolyzed in vivo, contain a freecarboxyl group or amine group.

[0101] Also of interest are hydrophobic amino acids such as mono-ordi-alkyl or aryl amino acids, cycloalkylamino acids and the like. Theseresidues, together with R²⁹-R³⁴ (R³¹-R³⁴ are defined below) cancontribute to cell permeability by modulating the lipophilicity of aformula 1 or formula 2 compound. Typically, the residue does not containa sulfhydryl or guanidino substituent.

[0102] Peptide.

[0103] One, 2, 3 or more of R¹-R⁴ can comprise a “peptide”, i.e., two ormore amino acids as defined above. Typically the amino acids are linkedthrough normal peptide bonds, i.e., —CO—NH—, between adjacent amino acidresidues. Peptides comprise dipeptides (dimers), tripeptides (trimers),short peptides of 4, 5, 6, 8, 10 or 15 residues, and longer peptides orproteins having about 100 or more residues. Invention compounds thatcomprise a peptide can be used as immunogens, prodrugs or as syntheticprecursors for other steroid derivatives. In one embodiment, the peptidewill contain a peptidolytic enzyme cleavage site at the peptide bondlinking the first residue and the next residue distal to the steroidresidue. Such cleavage sites are optionally flanked by enzymaticrecognition structures, e.g. particular residues recognized by ahydrolytic enzyme, e.g., a peptidase located in the serum or in cells.

[0104] Peptidolytic enzymes are well known, and in particular includecarboxypeptidases. Carboxypeptidases digest polypeptides by removingC-terminal residues, and are specific in many instances for particularC-terminal sequences. Such enzymes and their substrate requirements ingeneral are well known. For example, a dipeptide having a given pair ofresidues and a free carboxyl terminus is covalently bonded through itsα-amino group to the steroid nucleus. It is expected that the peptidewill be cleaved by the appropriate dipeptidase, protease or by chemicalhydrolysis, leaving the carboxyl of the proximal amino acid residue toautocatalytically cleave the amidate bond.

[0105] Examples of suitable dipeptidyl groups (designated by theirsingle letter symbols) are shown in the table below. SYMBOL 1-Letter3-Letter AMINO ACID Y Tyr tyrosine G Gly glycine F Phe phenylalanine MMet methionine A Ala alanine S Ser serine I Ile isoleucine L Leu leucineT Thr threonine V Val valine P Pro proline K Lys lysine H His histidineQ Gln glutamine E Glu glutamic acid W Trp tryptophan R Arg arginine DAsp aspartic acid N Asn asparagine C Cys cysteine

Dipeptides

[0106] AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS,AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF,RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK,NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI,DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG,CH, CI, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE,EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD,QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, OP, QS, QT, QW, QY, QV, GA, GR,GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV,HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW,HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS,IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF,LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK,KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI,ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG,FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE,PQ, pg, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD,SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR,TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV,WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW,WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS,YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF,VP, VS, VT, VW, VY, VV

[0107] Such dipeptides include species where both amino acids are in theL configuration, the D configuration or mixtures of configurations.

[0108] Tripeptides, i.e., 3 linked amino acid residues, are also usefulembodiments. Tripeptides include those where A, C, D, E, F, G, H, I, K,L, M, N, P, Q, R, S, T, V, W or Y is linked by a standard peptide bondto the amino or the carboxyl terminus of any of the dipeptides listedabove. The sequence —X1-pro-X2— (where X1 is any amino acid and X2 ishydrogen, any amino acid residue or a carboxyl ester of proline) will becleaved by luminal carboxypeptidase to yield X1 with a free carboxyl,which in turn autocatalytically cleaves the amidate bond. X2 usuallywill be a benzyl ester of the carboxy group of X2. Other embodimentsinclude tetrapeptides such as ones where any two of the dipeptideslisted above, which may be the same or different dipeptides (e.g., AAand AA linked together or, e.g., AA and GI linked together), are linkedto each other by a peptide bond through the amino terminus or carboxylterminus. One, 2 or more tetrapeptides may bonded to the formula 1 orformula 2 compound through the tetrapeptide's amino or carboxylterminus.

[0109] In some embodiments, the formula 1 or formula 2 compoundcomprises one or more amino acids or peptides having the structure (A),(B) or (C): (A)R³²—NH—{[C(R²⁹)(R³⁰)]_(b)—C(O)—N(R³¹)}_(f)—[C(R²⁹)(R³⁰)]_(a)—C(O)—O-steroid,(B) R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(g)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—O-steroid, or (C)R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(e)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—C(O)—O-steroid, wherein (A), (B) or (C) are independently selectedand they are bonded to 1, 2, 3 or more of R¹ through R⁴, where eachR²⁹-R³¹ is independently selected; R²⁹ independently are —H or a C1-20organic moiety (e.g., C₁₋₆ alkyl, e.g. —CH₃ or —C₂H₅); R³⁰ independentlyare the side chain of an amino acid, including the side chain ofnaturally occurring amino acids as described above, e.g., —H, —CH₃,—CH₂C₆H₅; R³¹ is —H or a protecting group; R³² and R³³ independentlycomprise —H, a protecting group, an ester or an amide where each atom orgroup is independently chosen; a, b, c and d independently are 1, 2, 3,4 or 5, usually 1; e, f and g independently are an integer from 0 toabout 1000, typically they independently are 0, 1, 2, 3, 4, 5, 6, 7 or8; a, b, c and d independently are 1 or 2; e, f and g independently are0, 1, 2, 3, 4 or 5.

[0110] If the amino acid(s) or residue(s) has 2 or more amine groups,e.g., a lysinyl or arginyl, or ornithinyl residue, then R²⁹ is usually—H and R³⁰ may comprise —[C(R³⁴)₂]_(n2)N(R^(PR))— where n2 is 0, 1, 2,3, 4, 5 or 6, R^(PR) is —H or a protecting group and each R³⁴independently is —H, C₁-C₂₀ optionally substituted alkyl, C₆-C₂₀optionally substituted aryl, C₇-C₂₀ optionally substituted alkylaryl,C₇-C₂₀ optionally substituted arylalkyl, C₁-C₂₀ optionally substitutedalkoxy, C₆-C₂₀ optionally substituted aryloxy or hydroxyl. Suchcompounds will contain a plurality of steroid moieties. For example whenboth the epsilon (ε) or delta (δ) and alpha (α) amino groups of lysineor ornithine are substituted with steroid moieties the amidate isbelieved to be capable of releasing two molecules of active drug, eachexpected to emerge under different pharmacokinetics and thereforefurther sustaining the drug release.

[0111] Salt.

[0112] Invention embodiments include salts and complexes of inventioncompounds (formula 1 compounds), including pharmaceutically acceptableor salts that are relatively non-toxic. Some of the invention compoundshave one or more moieties that carry at least a partial positive ornegative charge in aqueous solutions, typically at a pH of about 4-10,that can participate in forming a salt, a complex, a composition withpartial salt and partial complex properties or other noncovalentinteractions, all of which we refer to as a “salt(s)”. Salts are usuallybiologically compatible or pharmaceutically acceptable or non-toxic,particularly for mammalian cells. Salts that are biologically toxic areoptionally used with synthetic intermediates of invention compounds.When a water-soluble composition is desired, monovalent salts areusually used.

[0113] Metal salts typically are prepared by reacting the metalhydroxide with a compound of this invention. Examples of metal saltsthat are optionally prepared in this way are salts containing Li⁺, Na⁺,and K⁺. A less soluble metal salt can be precipitated from the solutionof a more soluble salt by adding a suitable metal compound. Inventionsalts may be formed from acid addition of certain organic acids, such asorganic carboxylic acids, and inorganic acids, such as alkylsulfonicacids or hydrogen halide acids, to acidic or basic centers on inventioncompounds, such as basic centers on the invention pyrimidine baseanalogs. Metal salts include ones containing Na⁺, Li⁺, K⁺, Ca⁺⁺ or Mg⁺⁺.Other metal salts may contain aluminum, barium, strontium, cadmium,bismuth, arsenic or zinc ion.

[0114] Salt(s) of invention compounds may comprise a combination ofappropriate cations such as alkali and alkaline earth metal ions orammonium and quaternary ammonium ions with the acid anion moiety of thephosphoric acid or phosphonic acid group, which may be present ininvention polymers or monomers.

[0115] Salts are produced by standard methods, including dissolving freebase in an aqueous, aqueous-alcohol or aqueous-organic solutioncontaining the selected acid, optionally followed by evaporating thesolution. The free base is reacted in an organic solution containing theacid, in which case the salt usually separates directly or one canconcentrate the solution.

[0116] Suitable amine salts include amines having sufficient basicity toform a stable salt, usually amines of low toxicity including trialkylamines (tripropylamine, triethylamine, trimethylamine), procaine,dibenzylamine, N-benzyl-betaphenethylamine, ephenamine,N,N′-dibenzylethylenediamine, N-ethylpiperidine, benzylamine anddicyclohexylamine.

[0117] Salts include organic sulfonic acid or organic carboxylic acidsalts, made for example by addition of the acids to basic centers,typically amines. Exemplary sulfonic acids include C₆₋₁₆ aryl sulfonicacids, C₆₋₁₆ heteroaryl sulfonic acids and C₁₋₁₆ alkyl sulfonic acidssuch as phenyl sulfonic acid, α-naphthalene sulfonic acid, β-naphthalenesulfonic acid, (S)-camphorsulfonic acid, methyl (CH₃SO₃H), ethyl(C₂H₅SO₃H), n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl,pentyl and hexyl sulfonic acids. Exemplary organic carboxylic acidsinclude C₁₋₁₆ alkyl, C₆₋₁₆ aryl carboxylic acids and C₄₋₁₆ heteroarylcarboxylic acids such as acetic, glycolic, lactic, pyruvic, malonic,glutaric, tartaric, citric, fumaric, succinic, malic, maleic, oxalic,hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicylic, nicotinic and 2-phenoxybenzoic.

[0118] Invention salts include those made from inorganic acids, e.g.,HF, HCl, HBr, HI, H₂SO₄, H₃PO₄, Na₂CO₃, K₂CO₃, CaCO₃, MgCO₃ and NaClO₃.Suitable anions, which are optionally present with a cation such a Ca⁺⁺,Mg⁺⁺, Li⁺, Na⁺ or K⁺, include arsenate, arsenite formate, sorbate,chlorate, perchlorate, periodate, dichromate, glycodeoxycholate,cholate, deoxycholate, desoxycholate, taurocholate, taurodeoxycholate,taurolithocholate, tetraborate, nitrate, nitrite, sulfite, sulfamate,hyposulfite, bisulfite, metabisulfite, thiosulfate, thiocyanate,silicate, metasilicate, CN⁻, gluconate, gulcuronate, hippurate, picrate,hydrosulfite, hexafluorophosphate, hypochlorite, hypochlorate, borate,metaborate, tungstate and urate.

[0119] Salts also include the invention compound salts with one or moreamino acids. Many amino acids are suitable, especially thenaturally-occurring amino acids found as protein components, althoughthe amino acid typically is one bearing a side chain with a basic oracidic group, e.g., lysine, arginine, histidine or glutamic acid, or aneutral group such as glycine, serine, threonine, alanine, isoleucine,or leucine.

[0120] The invention compositions include compounds in their un-ionized,as well as zwitterionic form, and combinations with stoiochimetricamounts of water as in hydrates.

[0121] Stereoisomers.

[0122] The compounds of the invention (formula 1 compounds) includeenriched or resolved optical isomers at any or all asymmetric atoms asare apparent from the depictions. Both racemic and diasteromericmixtures, as well as the individual optical isomers can be isolated orsynthesized so as to be substantially free of their enantiomeric ordiastereomeric partners, and these are all within the scope of theinvention. Chiral centers may be found in invention compounds at, forexample, R¹, R², R³ and R⁴.

[0123] One or more of the following methods are used to prepare theenantiomerically enriched or pure isomers herein. The methods are listedin approximately their order of preference, i.e., one ordinarily shouldemploy stereospecific synthesis from chiral precursors beforechromatographic resolution before spontaneous crystallization.

[0124] Stereospecific synthesis is described in the examples. Methods ofthis type conveniently are used when the appropriate chiral startingmaterial is available and reaction steps are chosen do not result inundesired racemization at chiral sites. One advantage of stereospecificsynthesis is that it does not produce undesired enantiomers that must beremoved from the final product, thereby lowering overall syntheticyield. In general, those skilled in the art would understand whatstarting materials and reaction conditions should be used to obtain thedesired enantiomerically enriched or pure isomers by stereospecificsynthesis.

[0125] If a suitable stereospecific synthesis cannot be empiricallydesigned or determined with routine experimentation then those skilledin the art would turn to other methods. One method of general utility ischromatographic resolution of enantiomers on chiral chromatographyresins. These resins are packed in columns, commonly called Pirklecolumns, and are commercially available. The columns contain a chiralstationary phase. The racemate is placed in solution and loaded onto thecolumn, and thereafter separated by HPLC. See for example, ProceedingsChromatographic Society—International Symposium on Chiral Separations,Sep. 3-4, 1987. Examples of chiral columns that could be used to screenfor the optimal separation technique would include Diacel Chriacel OD,Regis Pirkle Covalent D-phenylglycine, Regis Pirkle Type 1A, AstecCyclobond II, Astec Cyclobond III, Serva Chiral D−DL=Daltosil 100,Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate column,Astec Cyclobond I-Beta, or Regis Pirkle Covalent D-Naphthylalanine. Notall of these columns are likely to be effective with every racemicmixture. However, those skilled in the art understand that a certainamount of routine screening may be required to identify the mosteffective stationary phase. When using such columns it is desirable toemploy embodiments of the compounds of this invention in which thecharges are not neutralized, e.g., where acidic functionalities such ascarboxyl are not esterified or amidated.

[0126] Another method entails converting the enantiomers in the mixtureto diasteriomers with chiral auxiliaries and then separating theconjugates by ordinary column chromatography. This is a very suitablemethod, particularly when the embodiment contains free carboxyl, aminoor hydroxyl that will form a salt or covalent bond to a chiralauxiliary. Chirally pure amino acids, organic acids or organosulfonicacids are all worthwhile exploring as chiral auxiliaries, all of whichare well known in the art. Salts with such auxiliaries can be formed, orthey can be covalently (but reversibly) bonded to the functional group.For example, pure D or L amino acids can be used to amidate the carboxylgroup of invention embodiments that comprise a carboxyl group and thenseparated by chromatography.

[0127] Enzymatic resolution is another method of potential value. Insuch methods one prepares covalent derivatives of the enantiomers in theracemic mixture, generally lower alkyl esters (for example of carboxyl),and then exposes the derivative to enzymatic cleavage, generallyhydrolysis. For this method to be successful an enzyme must be chosenthat is capable of stereospecific cleavage, so it is frequentlynecessary to routinely screen several enzymes. If esters are to becleaved, then one selects a group of esterases, phosphatases, andlipases and determines their activity on the derivative. Typicalesterases are from liver, pancreas or other animal organs, and includeporcine liver esterase.

[0128] If the enatiomeric mixture separates from solution or a melt as aconglomerate, i.e., a mixture of enantiomerically pure crystals, thenthe crystals can be mechanically separated, thereby producing theenantiomerically enriched preparation. This method, however, is notpractical for large-scale preparations and is of limited value for trueracemic compounds.

[0129] Asymmetric synthesis is another technique for achievingenantiomeric enrichment. For example, a chiral protecting group isreacted with the group to be protected and the reaction) mixture allowedto equilibrate. If the reaction is enantiomerically specific then theproduct will be enriched in that enantiomer.

[0130] Further guidance in the separation of enantiomeric mixtures canbe found, by way of example and not limitation, in “Enantiomers,Racemates, and resolutions”, Jean Jacques, Andre Collet, and Samuel H.Wilen (Krieger Publishing Company, Malabar, Fla., 1991, ISBN0-89464-618-4): Part 2, Resolution of Enantiomer Mixture, pages 217-435;more particularly, section 4, Resolution by Direct Crystallization,pages 217-251, section 5, Formation and Separation of Diastereomers,pages 251-369, section 6, Crystallization-Induced AsymmetricTransformations, pages 369-378, and section 7, Experimental Aspects andArt of Resolutions, pages 378-435; still more particularly, section5.1.4, Resolution of Alcohols, Transformation of Alcohols intoSalt-Forming Derivatives, pages 263-266, section 5.2.3, CovalentDerivatives of Alcohols, Thiols, and Phenols, pages 332-335, section5.1.1, Resolution of Acids, pages 257-259, section 5.1.2, Resolution ofBases, pages 259-260, section 5.1.3, Resolution of Amino Acids, page261-263, section 5.2.1, Covalent Derivatives of Acids, page 329, section5.2.2, Covalent derivatives of Amines, pages 330-331, section 5.2.4,Covalent Derivatives of Aldehydes, Ketones, and Sulfoxides, pages335-339, and section 5.2.7, Chromatographic Behavior of CovalentDiastereomers, pages 348-354.

[0131] Unless otherwise stated or implied by context, expressions of apercentage of a liquid ingredient, e.g., an excipient, in an inventioncomposition or formulation mean the ingredient's percent by volume(v/v). Thus, 20% propylene glycol means 20% v/v propylene glycol ispresent in an invention composition or formulation. The amount ofexcipient indicated in invention compositions is not affected by theform used, e.g., NF or USP grade solvent or excipient. Thus, aninvention composition that comprises about 30% polyethylene glycol 300NF can instead comprise a USP counterpart, provided that otherlimitations, such as the amount of water present, are not exceeded.

[0132] As used herein, “innate immunity” refers to one or morecomponents typically associated with nonspecific immune defensemechanisms in a subject. These components include the alternatecomplement pathway, e.g., Factor B, Factor D and properdin; NK cells,phagocytes (monocytes, macrophages), neutrophils, eosinophils, dendriticcells, fibrocytes; anti-microbial chemicals, e.g., defensins; physicalbarriers—skin, mucosal epithelium; and certain interleukins, chemokinesand cytokines. Innate immunity plays a role in resistance tointracellular parasite infections, e.g., white blood cell infection, aliver infection, and other infections, e.g., lymph node infections.Enhancement of innate immunity mechanism by formula 1 compounds ormethod described herein may enhance phagolysosome fusion or movement,which some pathogens, e.g., intracellular bacteria such as mycobacteria,or Listeria inhibit.

[0133] As used herein, references to CD molecules, specific immune cellsubsets, immune responses and the like, generally use nomenclature thatapplies to molecules, cells or the like that are found in humans.Analogs or counterparts of such molecules, cells or the like in otherspecies may have a differing nomenclature, but are included in thisinvention. A description of the nomenclature and function of various CDmolecules and immune cell subsets are as found in the scientificliterature. References to Th0, Th1 or Th2 cells and references to Th1 orTh2 immune responses in the context of human patients refers to thehuman counterparts of the murine Th0, Th1 or Th2 immune cells orresponses. For reviews see, e.g., A. K. Abbas et al., editors, Cellularand Molecular Immunology, W. B. Saunders Company, third edition, 1997,ISBN 0-7216-4024-9, pages 4-469, and 1. Kimber and M. K. Selgrade,editors, T Lymphocyte Subpopulations in Immunotoxicology, John Wiley &Sons Ltd., 1998, ISBN 0-471-97194-4, pages 1-53.

[0134] “Immunosuppressive molecule” means molecules such as cyclosporin,cyclohexamide, mitomycin C, adriamycin, taxol and amphotericin B. Thesemolecules tend to have toxicities toward the immune system and aredirectly or indirectly immunosuppressive, i.e., toxic to dividing cellsor they can downregulate immunity.

[0135] “Steroid receptor” means a gene product, typically a proteinmonomer or dimer that can bind to a ligand, e.g., a natural steroid oran analog thereof, such as formula 1 compounds. Steroid receptorsinclude orphan steroid receptors. Orphan steroid receptors are proteinsfor which the natural ligand or biological function is at leastpartially unknown. As used here, steroid receptors include homodimers,e.g., SXR and (CARβ)₂, and heterodimers, e.g., PXR-CARβ or RXR-CARβ.Steroid receptors also include isoforms, e.g., PXR.1 and PXR.2 for thePXR receptor, and homologs of the steroid receptors, e.g., the homologof CARβ known as MB67. Isoforms are typically generated by differentsplicing pathways for a nuclear RNA from one gene, while homologs aretypically a distinct copy of a steroid receptor gene, where the genecopy encodes only relatively small differences compared to the referencesteroid receptor gene product. Such differences are most often found inareas other than the dimerization region and the steroid binding regionof the steroid receptor's structure. Typically isoforms and homologsbind the same or similar ligands as the reference gene product orsteroid receptor. Steroid receptors may be of human or animal origin,e.g., obtained from cells, tissues or cDNA expression libraries derivedfrom cells or tissues of any primate, rodent (including murine), avian,ovine, bovine, equine, canine or feline species or any of the species orany species within any group (e.g., Family or Genus) of speciesmentioned elsewhere herein or in any reference cited herein.

[0136] In the context of a combination of molecules that includes asteroid receptor and a formula 1 compound, “invention complexes” or“complexes” means a complex that comprises a steroid receptor and aformula 1 compound and optionally other molecules. These other moleculesinclude (i) a DNA recognition sequence (“DNARS” hereafter), i.e., asequence that the steroid receptor specifically recognizes and binds toand (ii) a transcription factor that can bind to the steroidreceptor-formula 1 compound complex. As used herein, these complexes canarise in cells in vitro or in vivo, or in cell-free systems. Complexesinclude, for example, steroid receptor heterodimer-formula 1 compoundcombinations, steroid receptor homodimer-formula 1 compoundcombinations, steroid receptor monomer-formula 1 compound combinations,steroid receptor heterodimer-formula 1 compound-DNA (or DNARS)combinations, steroid receptor homodimer-formula 1 compound-DNA (orDNARS) combinations, steroid receptor heterodimer-formula 1compound-transcription factor combinations, steroid receptorhomodimer-formula 1 compound-transcription factor combinations, steroidreceptor heterodimer-formula 1 compound-DNA (or DNARS)-transcriptionfactor combinations and steroid receptor homodimer-formula 1compound-DNA (or DNARS)-transcription factor combinations.

[0137] An “agonist” or an “antagonist” is a compound or composition thatrespectively, either increases or decreases the activity of a receptor,which can lead to increased or decreased transcription of a regulatedgene. Receptors (and transcription factors) can modulate transcriptionof their target gene(s) by enhancing transcription or decreasing it.

[0138] General Methods.

[0139] Methods have been described, for example Karl Fischer (KF) andloss on drying (LOD), to determine the content of water or solvents invarious compositions. LOD measures all volatiles in a sample, while KFis typically used to measure all water. When water is the only volatilepresent, LOD values are equal to or less than KF values for a givencomposition. KF measures water in hydrates of a compound and LODdetermines both water and the amount of other volatiles that may bepresent. Invention compositions and formulations are convenientlyassayed for water content by KF titration (e.g., using a Metrohm 684 KFCoulometer or equivalent) according to a published procedure (U.S.Pharmacopoeia, vol. 23, 1995, chapter <921>, U.S. PharmacopeialConvention, Inc., Rockville, Md.) and manufacturer's Coulometerinstructions. The amount of material used in the assay, about 50-100 mg,is measured using a five place analytical balance (Sartorius, Model RC21OD, or a suitable equivalent). The amounts of water specified ininvention compositions and formulations is the amount obtained by KFanalysis.

[0140] Powder X-ray diffraction (XRD) methods have been used tocharacterize various crystalline compounds (see, e.g., U.S.Pharmacopoeia, volume 23, 1995, <941>, p.1843-1845, U.S. PharmacopeialConvention, Inc., Rockville, Md.; Stout et al., X-Ray StructureDetermination; A Practical Guide, MacMillan Co., New York, N.Y., 1986).The diffraction pattern, or portions thereof, obtained from acrystalline compound is usually diagnostic for a given crystal form,although weak or very weak diffraction peaks may not always appear inreplicate diffraction patterns obtained from successive batches ofcrystals. Also, the relative intensities of XRD bands, particularly atlow angle X-ray incidence values (low Theta), may vary due to preferredorientation effects arising from differences in, e.g., crystal habit,particle size or other measurement conditions. Peaks on XRD spectra aretypically defined at a given Theta value +/− about 0.1 to 0.2. XRDinformation from the 1, 2, 3, 4, 5 or more main intensity XRD peaks,optionally combined with one or more other diagnostic data (meltingpoint, DSC, IR), is usually suitable to characterize or describe acrystalline material such as BrEA hemihydrate from other crystal formsthat contain the same compound.

[0141] Other techniques that are used to identify or describe acrystalline material such as BrEA hemihydrate include melting point(MP), differential scanning calorimetry (DSC) and infrared absorptionspectroscopy (IR) data. DSC measures thermal transition temperatures atwhich a crystal absorbs or releases heat when its crystal structurechanges or it melts. MP data and DSC thermal transition temperatures aretypically reproducible within about 1 or 2° C. on successive analyses.IR measures absorption of infrared light that is associated with thepresence of particular chemical bonds that are associated with groups,e.g., hydroxyl, that vibrate in response to particular lightwavelengths.

[0142] Invention Embodiments.

[0143] The invention provides BrEA hemihydrate, which is typicallysubstantially free of other forms of BrEA, such as amorphous BrEA oranhydrous BrEA. As used herein, BrEA hemihydrate or crystalline BrEAhemihydrate refers to solid BrEA and water having an ordered arrangementof substantially all of the constituent molecules in a definedthree-dimensional spatial pattern or lattice. Crystalline BrEAhemihydrate may comprise one or more crystal habits, e.g., tablets,rods, plates or needles. BrEA hemihydrate that is substantially free ofother forms of BrEA means a dry or substantially dry (where a liquid(s)comprises less than about 10% w/w of the total weight) solid preparationwhere more than about 55% w/w of the BrEA in the preparation is presentas BrEA hemihydrate. Such compositions typically comprise at least about60% w/w, or at least about 70% w/w, or at least about 80% w/w, usuallyat least about 90% w/w or at least about 95% w/w, or at least about 98%w/w of BrEA hemihydrate, with the remaining BrEA being present as otherforms of BrEA such as the amorphous or anhydrous BrEA. Solid BrEAhemihydrate will typically comprise at least about 90% w/w, usually atleast about 97% or about 98% w/w of the compound and less than about 10%w/w, usually less than about 3% or 2% w/w of by-products, which mayinclude the 16β isomer of BrEA or one or more by-products of BrEAsynthesis. Often the amount of solid BrEA that is present in a solid ora liquid medium will not contain detectable amounts of other forms ofBrEA (using standard analytical methods such as, e.g., FTIR, DSC or XRD)and the hemihydrate will may thus comprise about 99-100% w/w of thetotal amount of BrEA that is present.

[0144] Other invention embodiments include compositions that comprise asubstantial amount of BrEA hemihydrate that is present in compositionsthat comprise one or more other forms of BrEA, e.g., amorphous BrEA oranhydrous BrEA, and optionally one or more additional components, suchas any excipient described herein. As used herein, the “substantialamount” of BrEA hemihydrate in these compositions comprises at leastabout 15-20% w/w or at least about 20% w/w of BrEA hemihydrate of thetotal amount of BrEA that is present, typically at least about 25% w/w,more typically at least about 30% w/w, often at least about 35% w/w andusually at least about 45% w/w. These compositions are generally solids,e.g., formulations or unit dosages, but they also include suspensions,precipitates, gels and colloids that contain solid BrEA. Suchsuspensions or precipitates may arise from, e.g., precipitation of BrEAhemihydrate from a solution that contains water or from addition ofsolid BrEA to a liquid excipient(s). Obviously, compositions thatcomprise a substantial amount of BrEA may be substantially free of otherforms of solid BrEA as discussed above.

[0145] BrEA hemihydrate may conveniently be identified by reference toBrEA hemihydrate characterized by one or more of (1) its melting ordecomposition point or range (optionally expressed as +/− 2° C.), (2)one or more BrEA hemihydrate DSC transition temperatures or ranges (anyof which may be optionally expressed as +/−2° C.), (3) one or morecharacteristic BrEA hemihydrate IR absorption bands, (4) 1, 2, 3, 4, 5,6 or more of the highest intensity XRD peaks (any one or more of whichare optionally expressed as +/−0.10 Theta or +/−0.20 Theta) obtainedfrom an XRD spectrum of BrEA hemihydrate using Cu-Kα radiation (e.g.,obtained essentially according to the method described at U.S.Pharmacopoeia, volume 23, 1995, <941 >, p.1843-1845), (5) the presenceof less than about 3% or less than about 2% w/w of other compounds, (6)a water content of dry BrEA hemihydrate of about 2.5% w/w (e.g.,2.3-2.7% w/w), where dry BrEA hemihydrate means compound dried byfiltration, optionally washed once with an anhydrous solvent such ashexane, filtered again and dried in vacuo at about 60° C. until nofurther weight loss occurs over 24 hours at about 60° C. (e.g., wherewater content is determined essentially by the Karl Fisher or othermethod described at U.S. Pharmacopoeia, vol. 23, 1995, p 1801-1802 or1840-1843 methods <731 > or <921 >), (7) cell constants and theorientation matrix obtained from single crystal X-ray crystallography ofBrEA hemihydrate (obtained, e.g., essentially as described in WO99/04774 at example 13), (8) a description of crystal shapes as observedat about 100× magnification to about 150× magnification by polarizedlight microscopy or (9) average BrEA hemihydrate crystal size and shapedescriptions.

[0146] Thus, for example, BrEA hemihydrate may be characterized by orone or more of its IR absorption bands, e.g., the carbonyl peaks at 1741cm⁻¹ and 1752 cm⁻¹, and either its melting or decomposition point orrange and/or 1, 2, 3, 4, 5, 6 or more of the XRD peaks (usually thehighest intensity peaks) at Theta (X-ray diffraction angle) values of17.8, 23.8, 24.2, 26.9-27.2, 28.6, 30.1 and 32.2.

[0147] BrEA hemihydrate is suitable to prepare compositions comprisingan excipient(s) suitable for human pharmaceutical use or for veterinaryuse. Such compositions are used to prepare formulations and unitdosages. Unit dosages typically comprise tablets, capsules, lozenges orsterile solutions, including sterile solutions for parenteraladministration. Solid unit dosage forms typically comprise about 5-1000mg of BrEA hemihydrate, typically about 20-400 mg, e.g., about 25 mg,about 50 mg, about 100 mg, about 150 mg or about 250 mg per unit dose.

[0148] The invention provides a method to make BrEA hemihydratecomprising contacting water, 16α-bromo-3β-hydroxy-5α-androstan-17-oneand a C1-C6 alcohol (e.g., methanol, ethanol, propanol, isopropanol,butanol) and water. Typically the only one C1-C6 alcohol is present,e.g., ethanol, which is anhydrous or which may comprise up to about 2%w/w water. In some embodiments, the method utilizes a solution thatcomprises about 5-25% w/w water, about 30-45% w/w ethanol and about30-45% w/w of a BrEA preparation. Typical BrEA preparations are solidpreparations that comprise at least about 80% w/w, usually at leastabout 90% w/w or at least about 95% w/w of BrEA. The solutions maycomprise about 18-22% w/w water, about 37-43% w/w ethanol and about37-43% w/w of a BrEA preparation. In conducting the precipitation orcrystallization method, the solution will typically be at a temperatureof about −20° C. to about 45° C., usually at about 0° C. to about 20° C.The solution is maintained at this temperature range for about 30minutes to about 12 hours and the solution is optionally agitated usingslow to moderate agitation during crystallization.

[0149] A related embodiment comprises a method to prepare BrEAhemihydrate comprising precipitating BrEA from a solution comprising atleast about 15-25% w/w water, about 35-45% w/w of a BrEA preparation andat least about 35-45% w/w of one or more water-miscible solvents,typically C₁₋₆ alcohols (methanol, ethanol, propanol, isopropanol,butanol). The BrEA preparation may optionally comprise one or moreby-products of BrEA synthesis. Typical BrEA hemihydrate preparations orbatches comprise less than about 5% w/w, usually less than about 3% orabout 2% w/w of other compounds, such as by-products of BrEA synthesis.Aspects of this method include contacting water with an organic solutionthat comprises BrEA and an organic solvent such as a C1-C6 alcohol(e.g., ethanol) or acetone. Addition of water to such solutions leads toprecipitation of BrEA hemihydrate. Solutions that contain BrEAhemihydrate crystals or precipitate are invention embodiments that areused to prepare solid BrEA that is later dried and stored, typically atambient temperatures.

[0150] Precipitation of BrEA hemihydrate from water-containing solutionsis accomplished by known methods, e.g., reducing the solution'stemperature, using saturated or nearly saturated BrEA solutions, vacuumconcentration of saturated or nearly saturated BrEA solutions (which istypically conducted at a relatively low temperature, usually about15-25° C.), seeding with saturated or nearly saturated BrEA solutionswith BrEA hemihydrate crystals (e.g., about 10-100 mg per 1-10 L ofsolution), by heating a saturated or nearly saturated BrEA solution(about 25-35° C. for a few minutes followed by allowing the temperatureto fall or by actively cooling the solution) and optionally seeding thesolution with BrEA hemihydrate crystals or by addition of a liquid,e.g., additional water or ethanol, to a saturated or nearly saturatedBrEA ethanol-water solution, which causes the solution to becomesupersaturated. BrEA may also be precipitated from other solvents orsolvent systems, including acetone and acetone-ethanol. Such solventsare typically water miscible. Two-stage precipitation of BrEA may alsobe used to recover solid BrEA hemihydrate, e.g., initial precipitationand recovery of the solid, followed by either cooling and seeding of themother liquor or by allowing the mother liquor to stand, e.g., for aboutone, two or more days at ambient temperature, to obtain a second crop ofcrystals. Also, BrEA hemihydrate crystals may optionally berecrystallized, essentially as described herein, to further increase thepurity of the final solid. Methods for crystallizing organic compoundshave been described, e.g., A. S. Myerson, Handbook of IndustrialCrystallization, 1993, Butterworth-Heinemann, Stoneham, Mass., p 1-101.

[0151] Other related embodiments comprise a product produced by theprocess of contacting a solution comprising BrEA and an organic solventwith water. Typically the solutions are as described above, e.g., asolution comprising about 3-5% v/v water and at least about 40% v/v ofone or more water-miscible solvents, typically polar solvents such asC₁₋₆ alcohols or ketones (e.g., methanol, ethanol, propanol,isopropanol, butanol, typically ethanol or acetone). Such processes areaccomplished by any one or more of the techniques described in theparagraph above, e.g., cooling of a saturated or nearly saturated BrEAwater-ethanol solution and optionally seeding the cooled solution withBrEA hemihydrate. An embodiment related to this comprises solutions orsolids that comprise wet BrEA hemihydrate crystals or wet filtered orcentrifuged BrEA hemihydrate cakes, which may be obtained aftercrystallization. Examples of these embodiments include adding water to aBrEA-alcohol solution, e.g., slow addition of about 0.5-1.5 volumes orabout 0.8-1.2 volumes of water to about 6 volumes of a BrEA-ethanolsolution to obtain BrEA hemihydrate. Other examples of these embodimentsinclude adding water to a BrEA-ketone solvent solution, e.g., slowaddition of about 0.5-1.5 volumes or about 0.8-1.2 volumes of water toabout 10 volumes of a BrEA-acetone solution to obtain BrEA hemihydrate.

[0152] Another related embodiment is BrEA hemihydrate that is milled toan average particle size of about 0.01-200 μM, or about 0.1-10 μM orabout 0.5-5 μM. Average particle size or diameter for milled BrEAhemihydrate may thus be relatively small, e.g., about 0.03-2.0 μM orabout 0.1-1.0 μM, or somewhat larger, e.g., about about 0.5-5.0 μM orabout 1-5.0 μM. Milled BrEA hemihydrate is suitable for preparing solidformulations and parenteral formulations for human or veterinary use.The milled material facilitates dissolution of BrEA hemihydrate insolvents or excipients and facilitates mixing with solids or solidexcipients.

[0153] While it is possible to administer BrEA hemihydrate as a purecompound to a subject, it is usually presented as a solid formulation orused to prepare a liquid formulation. Formulations will typically beused to prepare unit dosages, e.g., tablets, capsules or lozenges fororal, buccal or sublingual administration, that comprise about 10-1000mg or typically about 25-400 mg of BrEA hemihydrate. Alternatively,embodiments include a product for parenteral (e.g., subcutaneous,subdermal, intravenous, intramuscular, intraperitoneal) administrationmade by the process of contacting BrEA hemihydrate and a liquidexcipient, e.g., any one, two, three or more of PEG 100, PEG 200, PEG300, PEG 400, propylene glycol, benzyl benzoate, benzyl alcohol orethanol, and optionally sterilizing the solution and optionallydispensing the solution into vials or ampules (typically amber glass),which may be single-use or multi-use and optionally storing theformulation at reduced temperature (about 0-12° C., or about 2-10° C.).Such products for parenteral administration typically comprise BrEA at aconcentration of about 10-170 mg/mL, usually at about 20-110 mg/mL orabout 30-100 mg/mL, and optionally one or more of a salt, buffer orbacteriostat or preservative (e.g., NaCl, BHA, BHT or EDTA).

[0154] Other embodiments include a product produced by the process ofcontacting BrEA hemihydrate, which may be substantially free of otherforms of BrEA, with an excipient suitable for human pharmaceutical useor for veterinary use. The product is useful to make formulations orunit dosage forms that contain the hemihydrate.

[0155] Formulations made from or containing BrEA hemihydrate willusually be stored under conditions that limit the amount of water thatreaches the formulation, e.g., silica gel in a sealed container thatholds a formulation. Water permeation characteristics of containers havebeen described, e.g., Containers—Permeation, Chapter, USP 23, 1995, U.S.Pharmacopeial Convention, Inc., Rockville, Md., p.1787.

[0156] Embodiments include invention compositions that transiently occurwhen a method step or operation is performed. For example, when aformula 1 compound such as BrEA, containing less than about 3% water iscontacted with an excipient, e.g., a PEG, an alcohol, propylene glycolor benzyl benzoate, the composition before addition of one ingredientwith another is a non-homogenous mixture. As the ingredients arecontacted, the mixture's homogeneity increases and the proportion ofingredients relative to each other approaches a desired value. Thus,invention compositions, which contain less than about 3% water cancomprise about 0.0001-99% of a formula 1 compound such as BrEA and oneor more excipients. These transient compositions are intermediates thatnecessarily arise when one makes an invention composition or formulationand they are included in invention embodiments to the extent that theyare patentable.

[0157] In general, the formula 1 compound that is present in inventioncompositions and formulations is completely dissolved in the non-aqueousexcipients. However, in some embodiments, e.g., transient compositionsand some formulations, the formula 1 compound is partially dissolvedwhile the remaining portion is present as a solid, which can be asuspension or a colloid.

[0158] Invention compositions and formulations suitable for parenteraldelivery of formula 1 compounds to humans or animals typically comprisetwo, three or more excipients. Exemplary embodiments include (1) anytwo, three or four of propylene glycol, PEG200, PEG300, ethanol andbenzyl benzoate and (2) any two, three or four of propylene glycol,PEG100, PEG200, PEG300, PEG400 and benzyl benzoate.

[0159] Invention compositions and formulations generally comprise about0.01-10% of BrEA, usually about 1-5%, and about 0.01-3% water, typicallyabout 0.05-3%, usually about 0.1-1 %. The invention formulations areusually presented as unit or multi-unit dosages suitable for parenteraladministration once or twice per day or once per 2-3 days. Unit dosagescomprise about 3-1000 mg of BrEA per unit dose, typically about 5-500mg, usually about 10-200 mg. For treating retroviruses such as HIV inhumans, a unit dose usually comprises about 10-250 mg of BrEA, usuallyabout 100-200 mg, in a volume of about 1-6 mL, usually about 2-4 mL.

[0160] Invention embodiments include the product made by a process ofcombining, mixing or otherwise contacting BrEA and one, two or moreexcipients. Such products are produced by routine methods of contactingthe ingredients. Such products optionally also contain a diluent, adisintegrant and a binder, or other excipients described herein or inreferences cited herein.

[0161] BrEA in the presence of significant amounts of water was found toepimerize at the bromine atom, leading to a mixture of the 16α- and16β-BrEA isomers. Invention compositions and formulations comprisingBrEA or BrEA hemihydrate will usually have a water content of less thanabout 3%, typically less than about 0.3%, usually less than about 0.1%.These compositions and formulations were found to have a good stabilitywhen stored at ambient temperature (about 5-40° C. as used herein) inclosed containers compared to control compositions and formulationshaving more water. Such liquids are also characterized by an unexpectedreduction in precipitation of the compound, which water appears toinduce.

[0162] Invention embodiments include compositions that comprise lessthan about 3% water, a formula 1 compound and a compound that is notgenerally considered suitable for human use but is useful to make aninvention formulation for veterinary use. Veterinary formulations arecompositions useful for the purpose of administering inventioncompositions to primates, cats, dogs, horses, cows, rabbits and othersubjects and may contain excipients acceptable in the veterinary art andare compatible with formula 1 compounds such as BrEA. These veterinarycompositions may not always be suitable for human use because theycontain an excipient that is not suitable for human use, e.g., analcohol other than ethanol such as methanol, propanol or butanol.Typically such excipients will be present at relatively low levels,e.g., about 1-30%, usually about 1-5%.

[0163] Invention embodiments include compositions and formulations,e.g., unit dosage forms and sterile solutions, that comprise (1) about1-100 mg/mL of a formula 1 compound(s), about 57.5% propylene glycol,about 25% PEG300, about 12.5% ethanol and about 5% benzyl benzoate; (2)about 1-60 mg/mL of a formula 1 compound(s), about 70% propylene glycol,about 25% PEG300 and about 5% benzyl benzoate; (3) about 1-60 mg/mL of aformula 1 compound(s), about 25% PEG300, about 35% propylene glycol,about 35% mannitol and about 5% benzyl benzoate; (4) about 1-60 mg/mL ofa formula 1 compound(s), about 57.5% propylene glycol, a mixturecomprising about 25% PEG300 and PEG200 (e.g., PEG300:PEG200 in a ratioof about 1:10 to about 10:1), about 12.5% ethanol and about 5% benzylbenzoate; (5) about 1-60 mg/mL of a formula 1 compound(s), about 75%propylene glycol, a mixture comprising about 25% PEG300 and PEG200(e.g., a PEG300:PEG200 in a ratio of about 1:10 to about 10:1) and about5% benzyl benzoate; (6) about 1-60 mg/mL of a formula 1 compound(s),about 25% PEG300 and PEG200 (e.g., PEG300:PEG200 in a ratio of about1:10 to about 10:1), about 35% propylene glycol, about 35% mannitol andabout 5% benzyl benzoate; (7) any of formulations (1) through (6) wherethe formula 1 compound(s) is about 40-55 mg/mL; (8) any of formulations(1) through (6) where the formula 1 compound(s) is about 30-100 mg/mL;(9) any of formulations (1) through (8) where 1, 2, 3 or 4 formula 1compounds are present; (10) any of formulations (1) through (8) where 1or 2 formula 1 compounds are present; (11) any of formulations (1)through (8) where 1 formula 1 compound is present; (12) any offormulations (1) through (11) where the formula 1 compound comprisesindependently at 1, 2 or 3 of any of R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ anindependently selected ester, thioester, carbonate, carbamate, aminoacid or peptide of 1 or 2 independently selected formula 1 compounds;(13) any of formulations (1) through (12) where the formula 1 compoundcomprises or is BrEA or BrEA hemihydrate; (14) any of formulations (1)through (13) where the formula 1 compound comprises or is an ester, asulfate ester or phosphoester of BrEA.

[0164] Other embodiments include the product obtained by storinginvention compositions or formulations, e.g., unit dosage forms, any ofembodiments (1)-(14) above, or compositions used to make formulations,at about 1 0-40° C. for at least about 3 days, e.g., storage at ambienttemperature for about 1-24 months. Invention formulations will typicallybe stored in hermetically or induction sealed containers for these timeperiods. Invention compositions will typically be held in closedcontainers. The specification and claims disclose exemplary suitableformulations and unit dosage forms for these embodiments.

[0165] Other embodiments include compounds compositions and formulationswhere one or more of R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ and R¹⁸ comprise an amino acidor a peptide, e.g., R¹, R² or R⁴ comprises an amino acid or a peptide,R³ is a halogen and R⁵ and R⁶ are both —CH₃. The peptide at one or moreof R¹-R⁶ can comprise a cell surface binding peptide such as the entireprotein or a sequence from fibronectin or retronectin, e.g., KQAGDV.

[0166] In the formula 1 compounds, each R⁴ is independently selected. Insome embodiments one R⁴ is hydrogen and the other is another moiety. Inother embodiments, both R⁴ are independently selected moieties otherthan hydrogen, e.g., a C1 to C20 organic moiety.

[0167] R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ and R¹⁸ include moieties, e.g., esters,thioesters, carbonates, amino acids, peptides and/or carbamates, thatare chemically and/or enzymatically hydrolyzable, often underphysiological conditions. Such moieties are independently chosen.Typically these moieties will give rise to —OH, —SH or —NH₂ at the R¹-R⁶positions of the steroid nucleus. Embodiments of formula 1 compoundsinclude ones where (1) one of R¹, R² and R⁴ is a hydrolyzable moiety(e.g., ester, thioester, carbonate, amino acid, peptide or carbamate),the other two of R¹, R² and R⁴ are —H, R³ is not hydrogen and R⁵ and R⁶are both —CH₃, (2) two of R¹, R² and R⁴ are hydrolyzable moieties (e.g.,independently chosen esters, thioesters, carbonates, amino acids,peptides and/or carbamates), the other of R¹, R² and R⁴ is —H, R³ is nothydrogen and R⁵ and R⁶ are both —CH₃, (3) R¹, R² and R⁴ are hydrolyzablemoieties, R³ is not hydrogen and R⁵ and R⁶ are both —CH₃. In theseembodiments, the R³ group is typically in the β-configuration and theR¹, R² and R⁴-R⁶ groups are typically in the α-configuration.

[0168] In other embodiments, one or more of R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ andR¹⁸, usually one, comprises an amino acid or a peptide, while theremaining groups are independently selected from the moieties definedherein. In these embodiments, the peptides are typically dimers(dipeptides) or trimers (tripeptides). For example one of R¹, R² or R⁴comprises an amino acid, the remaining of R¹, R² or R⁴ independentlycomprise —OH, ═O, an ester, a carbonate or a carbamate, while R³ is ahalogen, hydroxyl or an ester and R⁵ and R⁶ independently are —H,—(CH₂)_(m)—CH₃, —(CH₂)_(n)—CH₂OH, or —(CH₂)_(n)—CH₂F,—(CH₂)₂₋₄—O—(CH₂)₂₋₄—CH₃, where n is 0, 1, 2, 3, 4, 5, 6, 7 or 8 often0, 1, or 2, usually 0. Typically the ester, carbonate or carbamate arehydrolyzable under physiological conditions.

[0169] Hydrolyzable moieties typically comprise acyl groups, esters,ethers, thioethers, amides, amino acids, peptides, carbonates and/orcarbamates. In general, the structure of hydrolyzable moieties is notcritical and can vary. In some embodiments, these moieties contain atotal of about 4 to about 10 carbon atoms. These hydrolyzable moietiesin other embodiments comprise an organic moiety, as described above forester, that contains 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atomsand 1, 2, 3, 4, 5 or 6 heteroatoms, e.g., oxygen, nitrogen or sulfur.These hydrolyzable moieties can comprise no groups that are charged inplasma, blood, intracellular cytoplasm or in the gut, or they cancomprise 1, 2, 3 or more positive, negative or positive and negativecharges under one or more of these conditions. The charges may befractional depending on the group and the conditions it is under. Thesehydrolyzable moieties may comprise 1, 2, 3, 4 or more substitutions at ahydrogen atom(s) and/or a carbon atom(s), e.g., —OH, protected hydroxyl,—SH, protected thiol, carboxyl, protected carboxyl, amine, protectedamine, —O—, —S—, —CO—, —CS—, alkoxy, alkylthio, alkenyloxy, aryl,—OP(O)(O)—O—, —OS(O)(O)—O— and/or heterocycle. Such substitutions areindependently selected.

[0170] Formula 1 compounds that comprise a hydrolyzable moiety(ies) mayinclude one or more independently chosen —O—CHR²⁴C(O)OR²⁵,—S—CHR²⁴C(O)OR²⁵, —NH—CHR²⁴C(O)OR²⁵, —O—CHR²⁴C(S)OR²⁵, —S—CHR²⁴C(S)OR²⁵,—NH—CHR²⁴C(S)OR²⁵, —O—CHR²⁴OC(O)R²⁵, —S—CHR²⁴OC(O)R²⁵,—NH—CHR²⁴OC(O)R²⁵, —O—CHR²⁴C(O)N(R²⁵)₂, —S—CHR²⁴C(O)N(R²⁵)₂,—NH—CHR²⁴C(O)N(R²⁵)₂, —O—CHR²⁴OR²⁵, —S—CHR²⁴OR²⁵, —NH—CHR²⁴OR²⁵,—O—CHR²⁴C(R²⁵)₂CH₂OX, —S—CHR²⁴C(R²⁵)₂CH₂OX, —NH—CHR²⁴C(R²⁵)₂CH₂OX,—O—CHR²⁴C(R²⁵)₂OX, —S—CHR²⁴C(R²⁵)₂OX or —NH—CHR²⁴C(R²⁵)₂OX, groups thatone or more of R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ and R¹⁸ comprise. For thesehydrolyzable moieties, R²⁴ independently is —H, —CH₂-C₆H₅, —CH₂CH₂-C₆H₅,C₁₋₈ alkyl, C₂₋₈ alkenyl, aryl or heterocycle where each alkyl, alkenyl,aryl and heterocycle moiety is independently optionally substituted with1, 2, or 3, usually 1, —O—, —S—, —NH—, halogen, aryl, —OX, —SX, —NHX,ketone (═O) or —CN moieties or the C₁₋₈ alkyl is optionally substitutedwith 3, 4, 5 or 6 halogens, and X is —H or a protecting group. ExemplaryR²⁴ are —H, —CH₃, —C₂H₅, —CH₂—C₁₋₅ optionally substituted alkyl,—CH₂CH₂—C₁₋₄ optionally substituted alkyl and —CH₂CH₂—O—C₁₄ optionallysubstituted alkyl. R²⁵ independently is —H, —CH₂—C₆H₅, —CH₂CH₂—C₆H₅,C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, aryl, heterocycle, —CH₂-heterocycle or—CH₂-aryl, where each alkyl alkenyl, aryl, heterocycle, —CH₂-heterocycleor —CH₂-aryl moiety is independently optionally substituted with 1 or 2,usually 1, —O—, —S—, —NH—, halogen, aryl, —OX, —SX, —NHX, ketone (═O),—C(O)OX or —CN moieties or the C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl or aryl, areoptionally independently substituted with 3, 4, 5 or 6 halogens, where Xis —H or a protecting group, or the aryl, heterocycle, —CH₂-heterocycleor —CH₂-aryl moieties are optionally independently substituted with 1, 2or 3 C₁₋₄ alkyl moieties or with 1, 2 or 3 C₁₋₄ alkoxy moieties at thearyl moiety or at the heterocycle, usually at a ring carbon. ExemplaryR²⁵ are —H, —CH₃, —C₂H₅, —C₃H₇, —C₄H₉, —C₆H₁₃, —C₆H₅, —C₆H₄OH,—C₆H₄OCH₃, —C₆H₄F, —CH₂—C₁₋₅ optionally substituted alkyl, —CH₂CH₂—C₁₋₄optionally substituted alkyl and —CH₂CH₂—O—C₁₋₄ optionally substitutedalkyl.

[0171] Embodiments of formula 1 compounds include or exclude any subsetof compounds within the definition of formula 1, provided that at leastone compound remains. For example, a subset of formula 1 compounds thatare usually included, for example in the invention nonaqueousformulations and in the invention intermittent dosing protocols andimmune modulation methods, are formula 1 compounds where R² is hydroxyl,or a group that can hydrolyze to hydroxyl, in either configuration andR⁵ and R⁶ are methyl in the α-configuration. A subset compounds that areoptionally excluded from formula 1 compounds comprises one or allcompounds that are disclosed in one or more prior art references orpublications, e.g., one or more compounds that are disclosed in one ormore of the references cited herein, especially for those compounds thatcan render any claim or embodiment unpatentable for novelty, obviousnessand/or inventive step reasons.

[0172] Exemplary embodiments of species and genera of formula 1compounds are named as described below.

[0173] Group 1.

[0174] Exemplary embodiments include the formula 1 compounds namedaccording to the compound structure designations given in Tables A and Bbelow. Each compound named in Table B is depicted as a compound havingformula B

[0175] where R⁵ and R⁶ are both —CH₃, there is no double bond at the1-2-, 4-5- or 5-6-positions, one R⁴ is hydrogen, R⁷, R⁸ and R⁹ are all—CH₂— and R¹, R², R³ and R⁴ are the substituents designated in Table A.The compounds named according to Tables A and B are referred to as“group 1” compounds.

[0176] Compounds named in Table B are named by numbers assigned to R¹,R², R³ and R⁴ according to the following compound naming convention,R¹.R².R³.R⁴, based on the numbered chemical substituents depicted inTable A. Each Table A number specifies a different structure for each ofR¹, R², R³ and R⁴. When R¹, R², R³ or R⁴ is a divalent moiety, e.g., ═O,the hydrogen at the corresponding position is absent. Thus, the group 1compound named 1.2.1.1 is a formula B structure with a β-hydroxyl bondedto carbons at the 3- and 7-positions (the variable groups R¹ and R²respectively), an α-bromine bonded to carbon 16 (the variable group R³)and double bonded oxygen (═O) at carbon 17 (the variable group R⁴),i.e., 1.2.1.1 has the structure shown below. TABLE A

R¹ R² 1 —OH 1 —H 2 ═O 2 —OH 3 —SH 3 ═O 4 ═S 4 —CH₃ 5 —O—CH₃ 5 —OCH₃ 6—O—S(O)(O)—O⁻Na⁺ 6 —OC₂H₅ 7 —O—S(O)(O)—OC₂H₅ 7 —OCH₂CH₂CH₃ 8 —CH₃ 8—OCH₂CH₂CH₂CH₃ 9 —H 9 —Cl 10 —OC(O)C(CH₃)₃ 10 —Br R³ R⁴ 1 —Br 1 ═O 2 —Cl2 —OH 3 —I 3 —H 4 —F 4 —F 5 —H 5 —Cl 6 —OH 6 —Br 7 ═O 7 —I 8 —O—C(O)—CH₃8 —O—C(O)—CH₃ 9 —O—C(O)—CH₂CH₃ 9 —O—C(O)—CH₂CH₃ 10 —O—C(O)—CH₂CH₂CH₃ 10—O—C(O)—CH₂CH₂CH₃

[0177] TABLE B 1.1.1.1, 1.1.1.2, 1.1.1.3, 1.1.1.4, 1.1.1.5, 1.1.1.6,1.1.1.7, 1.1.1.8, 1.1.1.9, 1.1.1.10, 1.1.2.1, 1.1.2.2, 1.1.2.3, 1.1.2.4,1.1.2.5, 1.1.2.6, 1.1.2.7, 1.1.2.8, 1.1.2.9, 1.1.2.10, 1.1.3.1, 1.1.3.2,1.1.3.3, 1.1.3.4, 1.1.3.5, 1.1.3.6, 1.1.3.7, 1.1.3.8, 1.1.3.9, 1.1.3.10,1.1.4.1, 1.1.4.2, 1.1.4.3, 1.1.4.4, 1.1.4.5, 1.1.4.6, 1.1.4.7, 1.1.4.8,1.1.4.9, 1.1.4.10, 1.1.5.1, 1.1.5.2, 1.1.5.3, 1.1.5.4, 1.1.5.5, 1.1.5.6,1.1.5.7, 1.1.5.8, 1.1.5.9, 1.1.5.10, 1.1.6.1, 1.1.6.2, 1.1.6.3, 1.1.6.4,1.1.6.5, 1.1.6.6, 1.1.6.7, 1.1.6.8, 1.1.6.9, 1.1.6.10, 1.1.7.1, 1.1.7.2,1.1.7.3, 1.1.7.4, 1.1.7.5, 1.1.7.6, 1.1.7.7, 1.1.7.8, 1.1.7.9, 1.1.7.10,1.1.8.1, 1.1.8.2, 1.1.8.3, 1.1.8.4, 1.1.8.5, 1.1.8.6, 1.1.8.7, 1.1.8.8,1.1.8.9, 1.1.8.10, 1.1.9.1, 1.1.9.2, 1.1.9.3, 1.1.9.4, 1.1.9.5, 1.1.9.6,1.1.9.7, 1.1.9.8, 1.1.9.9, 1.1.9.10, 1.1.10.1, 1.1.10.2, 1.1.10.3,1.1.10.4, 1.1.10.5, 1.1.10.6, 1.1.10.7, 1.1.10.8, 1.1.10.9, 1.1.10.10,1.2.1.1, 1.2.1.2, 1.2.1.3, 1.2.1.4, 1.2.1.5, 1.2.1.6, 1.2.1.7, 1.2.1.8,1.2.1.9, 1.2.1.10, 1.2.2.1, 1.2.2.2, 1.2.2.3, 1.2.2.4, 1.2.2.5, 1.2.2.6,1.2.2.7, 1.2.2.8, 1.2.2.9, 1.2.2.10, 1.2.3.1, 1.2.3.2, 1.2.3.3, 1.2.3.4,1.2.3.5, 1.2.3.6, 1.2.3.7, 1.2.3.8, 1.2.3.9, 1.2.3.10, 1.2.4.1, 1.2.4.2,1.2.4.3, 1.2.4.4, 1.2.4.5, 1.2.4.6, 1.2.4.7, 1.2.4.8, 1.2.4.9, 1.2.4.10,1.2.5.1, 1.2.5.2, 1.2.5.3, 1.2.5.4, 1.2.5.5, 1.2.5.6, 1.2.5.7, 1.2.5.8,1.2.5.9, 1.2.5.10, 1.2.6.1, 1.2.6.2, 1.2.6.3, 1.2.6.4, 1.2.6.5, 1.2.6.6,1.2.6.7, 1.2.6.8, 1.2.6.9, 1.2.6.10, 1.2.7.1, 1.2.7.2, 1.2.7.3, 1.2.7.4,1.2.7.5, 1.2.7.6, 1.2.7.7, 1.2.7.8, 1.2.7.9, 1.2.7.10, 1.2.8.1, 1.2.8.2,1.2.8.3, 1.2.8.4, 1.2.8.5, 1.2.8.6, 1.2.8.7, 1.2.8.8, 1.2.8.9, 1.2.8.10,1.2.9.1, 1.2.9.2, 1.2.9.3, 1.2.9.4, 1.2.9.5, 1.2.9.6, 1.2.9.7, 1.2.9.8,1.2.9.9, 1.2.9.10, 1.2.10.1, 1.2.10.2, 1.2.10.3, 1.2.10.4, 1.2.10.5,1.2.10.6, 1.2.10.7, 1.2.10.8, 1.2.10.9, 1.2.10.10, 1.3.1.1, 1.3.1.2,1.3.1.3, 1.3.1.4, 1.3.1.5, 1.3.1.6, 1.3.1.7, 1.3.1.8, 1.3.1.9, 1.3.1.10,1.3.2.1, 1.3.2.2, 1.3.2.3, 1.3.2.4, 1.3.2.5, 1.3.2.6, 1.3.2.7, 1.3.2.8,1.3.2.9, 1.3.2.10, 1.3.3.1, 1.3.3.2, 1.3.3.3, 1.3.3.4, 1.3.3.5, 1.3.3.6,1.3.3.7, 1.3.3.8, 1.3.3.9, 1.3.3.10, 1.3.4.1, 1.3.4.2, 1.3.4.3, 1.3.4.4,1.3.4.5, 1.3.4.6, 1.3.4.7, 1.3.4.8, 1.3.4.9, 1.3.4.10, 1.3.5.1, 1.3.5.2,1.3.5.3, 1.3.5.4, 1.3.5.5, 1.3.5.6, 1.3.5.7, 1.3.5.8, 1.3.5.9, 1.3.5.10,1.3.6.1, 1.3.6.2, 1.3.6.3, 1.3.6.4, 1.3.6.5, 1.3.6.6, 1.3.6.7, 1.3.6.8,1.3.6.9, 1.3.6.10, 1.3.7.1, 1.3.7.2, 1.3.7.3, 1.3.7.4, 1.3.7.5, 1.3.7.6,1.3.7.7, 1.3.7.8, 1.3.7.9, 1.3.7.10, 1.3.8.1, 1.3.8.2, 1.3.8.3, 1.3.8.4,1.3.8.5, 1.3.8.6, 1.3.8.7, 1.3.8.8, 1.3.8.9, 1.3.8.10, 1.3.9.1, 1.3.9.2,1.3.9.3, 1.3.9.4, 1.3.9.5, 1.3.9.6, 1.3.9.7, 1.3.9.8, 1.3.9.9, 1.3.9.10,1.3.10.1, 1.3.10.2, 1.3.10.3, 1.3.10.4, 1.3.10.5, 1.3.10.6, 1.3.10.7,1.3.10.8, 1.3.10.9, 1.3.10.10, 1.4.1.1, 1.4.1.2, 1.4.1.3, 1.4.1.4,1.4.1.5, 1.4.1.6, 1.4.1.7, 1.4.1.8, 1.4.1.9, 1.4.1.10, 1.4.2.1, 1.4.2.2,1.4.2.3, 1.4.2.4, 1.4.2.5, 1.4.2.6, 1.4.2.7, 1.4.2.8, 1.4.2.9, 1.4.2.10,1.4.3.1, 1.4.3.2, 1.4.3.3, 1.4.3.4, 1.4.3.5, 1.4.3.6, 1.4.3.7, 1.4.3.8,1.4.3.9, 1.4.3.10, 1.4.4.1, 1.4.4.2, 1.4.4.3, 1.4.4.4, 1.4.4.5, 1.4.4.6,1.4.4.7, 1.4.4.8, 1.4.4.9, 1.4.4.10, 1.4.5.1, 1.4.5.2, 1.4.5.3, 1.4.5.4,1.4.5.5, 1.4.5.6, 1.4.5.7, 1.4.5.8, 1.4.5.9, 1.4.5.10, 1.4.6.1, 1.4.6.2,1.4.6.3, 1.4.6.4, 1.4.6.5, 1.4.6.6, 1.4.6.7, 1.4.6.8, 1.4.6.9, 1.4.6.10,1.4.7.1, 1.4.7.2, 1.4.7.3, 1.4.7.4, 1.4.7.5, 1.4.7.6, 1.4.7.7, 1.4.7.8,1.4.7.9, 1.4.7.10, 1.4.8.1, 1.4.8.2, 1.4.8.3, 1.4.8.4, 1.4.8.5, 1.4.8.6,1.4.8.7, 1.4.8.8, 1.4.8.9, 1.4.8.10, 1.4.9.1, 1.4.9.2, 1.4.9.3, 1.4.9.4,1.4.9.5, 1.4.9.6, 1.4.9.7, 1.4.9.8, 1.4.9.9, 1.4.9.10, 1.4.10.1,1.4.10.2, 1.4.10.3, 1.4.10.4, 1.4.10.5, 1.4.10.6, 1.4.10.7, 1.4.10.8,1.4.10.9, 1.4.10.10, 1.5.1.1, 1.5.1.2, 1.5.1.3, 1.5.1.4, 1.5.1.5,1.5.1.6, 1.5.1.7, 1.5.1.8, 1.5.1.9, 1.5.1.10, 1.5.2.1, 1.5.2.2, 1.5.2.3,1.5.2.4, 1.5.2.5, 1.5.2.6, 1.5.2.7, 1.5.2.8, 1.5.2.9, 1.5.2.10, 1.5.3.1,1.5.3.2, 1.5.3.3, 1.5.3.4, 1.5.3.5, 1.5.3.6, 1.5.3.7, 1.5.3.8, 1.5.3.9,1.5.3.10, 1.5.4.1, 1.5.4.2, 1.5.4.3, 1.5.4.4, 1.5.4.5, 1.5.4.6, 1.5.4.7,1.5.4.8, 1.5.4.9, 1.5.4.10, 1.5.5.1, 1.5.5.2, 1.5.5.3, 1.5.5.4, 1.5.5.5,1.5.5.6, 1.5.5.7, 1.5.5.8, 1.5.5.9, 1.5.5.10, 1.5.6.1, 1.5.6.2, 1.5.6.3,1.5.6.4, 1.5.6.5, 1.5.6.6, 1.5.6.7, 1.5.6.8, 1.5.6.9, 1.5.6.10, 1.5.7.1,1.5.7.2, 1.5.7.3, 1.5.7.4, 1.5.7.5, 1.5.7.6, 1.5.7.7, 1.5.7.8, 1.5.7.9,1.5.7.10, 1.5.8.1, 1.5.8.2, 1.5.8.3, 1.5.8.4, 1.5.8.5, 1.5.8.6, 1.5.8.7,1.5.8.8, 1.5.8.9, 1.5.8.10, 1.5.9.1, 1.5.9.2, 1.5.9.3, 1.5.9.4, 1.5.9.5,1.5.9.6, 1.5.9.7, 1.5.9.8, 1.5.9.9, 1.5.9.10, 1.5.10.1, 1.5.10.2,1.5.10.3, 1.5.10.4, 1.5.10.5, 1.5.10.6, 1.5.10.7, 1.5.10.8, 1.5.10.9,1.5.10.10, 1.6.1.1, 1.6.1.2, 1.6.1.3, 1.6.1.4, 1.6.1.5, 1.6.1.6,1.6.1.7, 1.6.1.8, 1.6.1.9, 1.6.1.10, 1.6.2.1, 1.6.2.2, 1.6.2.3, 1.6.2.4,1.6.2.5, 1.6.2.6, 1.6.2.7, 1.6.2.8, 1.6.2.9, 1.6.2.10, 1.6.3.1, 1.6.3.2,1.6.3.3, 1.6.3.4, 1.6.3.5, 1.6.3.6, 1.6.3.7, 1.6.3.8, 1.6.3.9, 1.6.3.10,1.6.4.1, 1.6.4.2, 1.6.4.3, 1.6.4.4, 1.6.4.5, 1.6.4.6, 1.6.4.7, 1.6.4.8,1.6.4.9, 1.6.4.10, 1.6.5.1, 1.6.5.2, 1.6.5.3, 1.6.5.4, 1.6.5.5, 1.6.5.6,1.6.5.7, 1.6.5.8, 1.6.5.9, 1.6.5.10, 1.6.6.1, 1.6.6.2, 1.6.6.3, 1.6.6.4,1.6.6.5, 1.6.6.6, 1.6.6.7, 1.6.6.8, 1.6.6.9, 1.6.6.10, 1.6.7.1, 1.6.7.2,1.6.7.3, 1.6.7.4, 1.6.7.5, 1.6.7.6, 1.6.7.7, 1.6.7.8, 1.6.7.9, 1.6.7.10,1.6.8.1, 1.6.8.2, 1.6.8.3, 1.6.8.4, 1.6.8.5, 1.6.8.6, 1.6.8.7, 1.6.8.8,1.6.8.9, 1.6.8.10, 1.6.9.1, 1.6.9.2, 1.6.9.3, 1.6.9.4, 1.6.9.5, 1.6.9.6,1.6.9.7, 1.6.9.8, 1.6.9.9, 1.6.9.10, 1.6.10.1, 1.6.10.2, 1.6.10.3,1.6.10.4, 1.6.10.5, 1.6.10.6, 1.6.10.7, 1.6.10.8, 1.6.10.9, 1.6.10.10,1.7.1.1, 1.7.1.2, 1.7.1.3, 1.7.1.4, 1.7.1.5, 1.7.1.6, 1.7.1.7, 1.7.1.8,1.7.1.9, 1.7.1.10, 1.7.2.1, 1.7.2.2, 1.7.2.3, 1.7.2.4, 1.7.2.5, 1.7.2.6,1.7.2.7, 1.7.2.8, 1.7.2.9, 1.7.2.10, 1.7.3.1, 1.7.3.2, 1.7.3.3, 1.7.3.4,1.7.3.5, 1.7.3.6, 1.7.3.7, 1.7.3.8, 1.7.3.9, 1.7.3.10, 1.7.4.1, 1.7.4.2,1.7.4.3, 1.7.4.4, 1.7.4.5, 1.7.4.6, 1.7.4.7, 1.7.4.8, 1.7.4.9, 1.7.4.10,1.7.5.1, 1.7.5.2, 1.7.5.3, 1.7.5.4, 1.7.5.5, 1.7.5.6, 1.7.5.7, 1.7.5.8,1.7.5.9, 1.7.5.10, 1.7.6.1, 1.7.6.2, 1.7.6.3, 1.7.6.4, 1.7.6.5, 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10.7.1.2, 10.7.1.3, 10.7.1.4, 10.7.1.5,10.7.1.6, 10.7.1.7, 10.7.1.8, 10.7.1.9, 10.7.1.10, 10.7.2.1, 10.7.2.2,10.7.2.3, 10.7.2.4, 10.7.2.5, 10.7.2.6, 10.7.2.7, 10.7.2.8, 10.7.2.9,10.7.2.10, 10.7.3.1, 10.7.3.2, 10.7.3.3, 10.7.3.4, 10.7.3.5, 10.7.3.6,10.7.3.7, 10.7.3.8, 10.7.3.9, 10.7.3.10, 10.7.4.1, 10.7.4.2, 10.7.4.3,10.7.4.4, 10.7.4.5, 10.7.4.6, 10.7.4.7, 10.7.4.8, 10.7.4.9, 10.7.4.10,10.7.5.1, 10.7.5.2, 10.7.5.3, 10.7.5.4, 10.7.5.5, 10.7.5.6, 10.7.5.7,10.7.5.8, 10.7.5.9, 10.7.5.10, 10.7.6.1, 10.7.6.2, 10.7.6.3, 10.7.6.4,10.7.6.5, 10.7.6.6, 10.7.6.7, 10.7.6.8, 10.7.6.9, 10.7.6.10, 10.7.7.1,10.7.7.2, 10.7.7.3, 10.7.7.4, 10.7.7.5, 10.7.7.6, 10.7.7.7, 10.7.7.8,10.7.7.9, 10.7.7.10, 10.7.8.1, 10.7.8.2, 10.7.8.3, 10.7.8.4, 10.7.8.5,10.7.8.6, 10.7.8.7, 10.7.8.8, 10.7.8.9, 10.7.8.10, 10.7.9.1, 10.7.9.2,10.7.9.3, 10.7.9.4, 10.7.9.5, 10.7.9.6, 10.7.9.7, 10.7.9.8, 10.7.9.9,10.7.9.10, 10.7.10.1, 10.7.10.2, 10.7.10.3, 10.7.10.4, 10.7.10.5,10.7.10.6, 10.7.10.7, 10.7.10.8, 10.7.10.9, 10.7.10.10, 10.8.1.1,10.8.1.2, 10.8.1.3, 10.8.1.4, 10.8.1.5, 10.8.1.6, 10.8.1.7, 10.8.1.8,10.8.1.9, 10.8.1.10, 10.8.2.1, 10.8.2.2, 10.8.2.3, 10.8.2.4, 10.8.2.5,10.8.2.6, 10.8.2.7, 10.8.2.8, 10.8.2.9, 10.8.2.10, 10.8.3.1, 10.8.3.2,10.8.3.3, 10.8.3.4, 10.8.3.5, 10.8.3.6, 10.8.3.7, 10.8.3.8, 10.8.3.9,10.8.3.10, 10.8.4.1, 10.8.4.2, 10.8.4.3, 10.8.4.4, 10.8.4.5, 10.8.4.6,10.8.4.7, 10.8.4.8, 10.8.4.9, 10.8.4.10, 10.8.5.1, 10.8.5.2, 10.8.5.3,10.8.5.4, 10.8.5.5, 10.8.5.6, 10.8.5.7, 10.8.5.8, 10.8.5.9, 10.8.5.10,10.8.6.1, 10.8.6.2, 10.8.6.3, 10.8.6.4, 10.8.6.5, 10.8.6.6, 10.8.6.7,10.8.6.8, 10.8.6.9, 10.8.6.10, 10.8.7.1, 10.8.7.2, 10.8.7.3, 10.8.7.4,10.8.7.5, 10.8.7.6, 10.8.7.7, 10.8.7.8, 10.8.7.9, 10.8.7.10, 10.8.8.1,10.8.8.2, 10.8.8.3, 10.8.8.4, 10.8.8.5, 10.8.8.6, 10.8.8.7, 10.8.8.8,10.8.8.9, 10.8.8.10, 10.8.9.1, 10.8.9.2, 10.8.9.3, 10.8.9.4, 10.8.9.5,10.8.9.6, 10.8.9.7, 10.8.9.8, 10.8.9.9, 10.8.9.10, 10.8.10.1, 10.8.10.2,10.8.10.3, 10.8.10.4, 10.8.10.5, 10.8.10.6, 10.8.10.7, 10.8.10.8,10.8.10.9, 10.8.10.10, 10.9.1.1, 10.9.1.2, 10.9.1.3, 10.9.1.4, 10.9.1.5,10.9.1.6, 10.9.1.7, 10.9.1.8, 10.9.1.9, 10.9.1.10, 10.9.2.1, 10.9.2.2,10.9.2.3, 10.9.2.4, 10.9.2.5, 10.9.2.6, 10.9.2.7, 10.9.2.8, 10.9.2.9,10.9.2.10, 10.9.3.1, 10.9.3.2, 10.9.3.3, 10.9.3.4, 10.9.3.5, 10.9.3.6,10.9.3.7, 10.9.3.8, 10.9.3.9, 10.9.3.10, 10.9.4.1, 10.9.4.2, 10.9.4.3,10.9.4.4, 10.9.4.5, 10.9.4.6, 10.9.4.7, 10.9.4.8, 10.9.4.9, 10.9.4.10,10.9.5.1, 10.9.5.2, 10.9.5.3, 10.9.5.4, 10.9.5.5, 10.9.5.6, 10.9.5.7,10.9.5.8, 10.9.5.9, 10.9.5.10, 10.9.6.1, 10.9.6.2, 10.9.6.3, 10.9.6.4,10.9.6.5, 10.9.6.6, 10.9.6.7, 10.9.6.8, 10.9.6.9, 10.9.6.10, 10.9.7.1,10.9.7.2, 10.9.7.3, 10.9.7.4, 10.9.7.5, 10.9.7.6, 10.9.7.7, 10.9.7.8,10.9.7.9, 10.9.7.10, 10.9.8.1, 10.9.8.2, 10.9.8.3, 10.9.8.4, 10.9.8.5,10.9.8.6, 10.9.8.7, 10.9.8.8, 10.9.8.9, 10.9.8.10, 10.9.9.1, 10.9.9.2,10.9.9.3, 10.9.9.4, 10.9.9.5, 10.9.9.6, 10.9.9.7, 10.9.9.8, 10.9.9.9,10.9.9.10, 10.9.10.1, 10.9.10.2, 10.9.10.3, 10.9.10.4, 10.9.10.5,10.9.10.6, 10.9.10.7, 10.9.10.8, 10.9.10.9, 10.9.10.10, 10.10.1.1,10.10.1.2, 10.10.1.3, 10.10.1.4, 10.10.1.5, 10.10.1.6, 10.10.1.7,10.10.1.8, 10.10.1.9, 10.10.1.10, 10.10.2.1, 10.10.2.2, 10.10.2.3,10.10.2.4, 10.10.2.5, 10.10.2.6, 10.10.2.7, 10.10.2.8, 10.10.2.9,10.10.2.10, 10.10.3.1, 10.10.3.2, 10.10.3.3, 10.10.3.4, 10.10.3.5,10.10.3.6, 10.10.3.7, 10.10.3.8, 10.10.3.9, 10.10.3.10, 10.10.4.1,10.10.4.2, 10.10.4.3, 10.10.4.4, 10.10.4.5, 10.10.4.6, 10.10.4.7,10.10.4.8, 10.10.4.9, 10.10.4.10, 10.10.5.1, 10.10.5.2, 10.10.5.3,10.10.5.4, 10.10.5.5, 10.10.5.6, 10.10.5.7, 10.10.5.8, 10.10.5.9,10.10.5.10, 10.10.6.1, 10.10.6.2, 10.10.6.3, 10.10.6.4, 10.10.6.5,10.10.6.6, 10.10.6.7, 10.10.6.8, 10.10.6.9, 10.10.6.10, 10.10.7.1,10.10.7.2, 10.10.7.3, 10.10.7.4, 10.10.7.5, 10.10.7.6, 10.10.7.7,10.10.7.8, 10.10.7.9, 10.10.7.10, 10.10.8.1, 10.10.8.2, 10.10.8.3,10.10.8.4, 10.10.8.5, 10.10.8.6, 10.10.8.7, 10.10.8.8, 10.10.8.9,10.10.8.10, 10.10.9.1, 10.10.9.2, 10.10.9.3, 10.10.9.4, 10.10.9.5,10.10.9.6, 10.10.9.7, 10.10.9.8, 10.10.9.9, 10.10.9.10, 10.10.10.1,10.10.10.2, 10.10.10.3, 10.10.10.4, 10.10.10.5, 10.10.10.6, 10.10.10.7,10.10.10.8, 10.10.10.9, 10.10.10.10

[0178] Additional exemplary formula B compound groups include thefollowing compound groups disclosed below. Unless otherwise specified,the configurations of all hydrogen atoms and R groups for the followingcompound groups are as defined for the group 1 compounds of formula Babove.

[0179] Group 2. This group comprises compounds named in Table B havingR¹, R², R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³and R⁴ substituents are bonded to the steroid nucleus described forgroup 1 compounds, except that a double bond at the 5-6 position ispresent. Thus, group 2 compound 1.3.1.1 has the structure

[0180] Group 3. This group comprises compounds named in Table B havingR¹, R², R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³and R⁴ substituents are bonded to the steroid nucleus as described forgroup 1 compounds, except that double bonds at the 1-2- and 5-6positions are present. Thus, group 3 compound 2.2.5.1 has the structure

[0181] Group 4.

[0182] This group comprises compounds named in Table B having R¹, R², R³and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 1-2 position is present.Thus, group 4 compound 5.2.7.8 has the structure

[0183] Group 5.

[0184] This group comprises compounds named in Table B having R¹, R², R³and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 4-5 position is present.Thus, the group 5 compound named 3.5.2.9 has the structure

[0185] Group 6.

[0186] This group comprises compounds named in Table B having R¹, R², R³and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at both the 1-2 and 4-5 positionsare present. Thus, the group 6 compound named 10.2.7.8 has the structure

[0187] Groups 7-1 through 7-6.

[0188] These groups comprise the 6 compound groups described above,except that R⁵ is hydrogen instead of methyl. Thus, group 7-1 has thesame steroid nucleus as group 1 above, i.e., no double bond is present,but R⁵ is —H. Group 7-2 comprises the same steroid nucleus as group 2above, i.e., a double bond is present at the 5-6-position, but R⁵ is —H.Compound groups 7-3 through 7-6 are assigned a steroid nucleus in thesame manner. Thus, the group 7-1 through group 7-6 compounds named1.2.1.9 have the structures

[0189] Groups 8-1 through 8-6.

[0190] These groups comprise each compound named in groups 1-6, exceptthat R⁵ of formula B is —CH₂OH instead of methyl. The groups 8-1 throughgroup 8-6 compounds have structures that are named in the same manner asgroup 1-6 compounds, except that —CH₂OH instead of methyl is present atR⁵. These groups are named in the same manner as groups 7-1 through 7-6.Thus, group 8-1 and group 8-2 compounds named 1.2.1.9 have thestructures

[0191] Groups 9-1 through 9-6. These groups comprise each compound namedin compound groups 1-6, except that R⁶ of formula B is hydrogen insteadof methyl. The groups 9-1 through group 9-6 compounds have structuresthat are named in the same manner as group 7-1 through 7-6 compounds,except that —H instead of methyl is present at R⁶. Thus, group 9-1 andgroup 9-2 compounds named 1.2.1.9 have the structures

[0192] Groups 10-1 through 10-6. These groups comprise each compoundnamed in compound groups 1-6 where R⁶ of formula 1 is —CH₂OH instead ofmethyl. The groups 10-1 through group 10-6 compounds have structuresthat are named in the same manner as group 7-1 through 7-6 compounds,except that —CH₂OH instead of methyl is present at R⁶. Thus, group 10-1and group 10-2 compounds named 1.2.1.9 have the structures

[0193] Groups 11-1 through 11-10-6. These groups comprise each compoundnamed in compound groups 1 through 10-6 where R¹ substituents 1-10listed in Table A are replaced with the following substituents:

[0194] 1—O—C(O)—CH₂CH₂CH₂CH₃ (—O—C(O)—CH₂CH₂CH₂CH₃ replaces —OH, whichis R¹ substituent 1 in Table A)

[0195] 2 —O—C(O)—CH₂CH₂CH₂CH₂CH₂CH₃

[0196] 3 —O—C(O)—CH₂CH₂OCH₂CH₃

[0197] 4 —O—C(O)—CH₂CH₂OCH₂CH₂OCH₂CH₃

[0198] 5 —O—C(O)—CH₂CH₂CH₂CH₂OCH₂CH₃

[0199] 6 —O—C(O)—CH₂CH₂OCH₂CH₂CH₂CH₃

[0200] 7 —O—C₆H₄Cl

[0201] 8 —O—C₆H₃F₂

[0202] 9 —O—C₆H₄—O(CH₂)₂—O—CH₂CH₃

[0203] 10 —O—C₆H₄—C(O)O(CH₂)₀₋₉CH₃

[0204] The group 11-1 through group 11-6 compounds have structures thatare named in the same manner as group 7-1 through 7-6 compounds, exceptthat substituents 1-10 of table A are replaced by the substituents 1-10at R¹ listed above. Thus group 11-1 and 11-2 compounds named 1.2.1.9have the structures

[0205] Group 11-7-1 and 11-7-2 compounds named 1.2.1.9 have thestructures

[0206] Group 11-8-1 and 11-8-2 compounds named 1.2.1.9 have thestructures

[0207] Groups 12-1 through 12-10-6.

[0208] These groups comprise each compound named in groups 1 through10-6 where R¹ substituents 1-10 listed in Table A are replaced with thefollowing groups:

[0209] 1 —O—P(O)(O)—OCH₂CH(CH₃)CH₃ (—O—P(O)(O)—OCH₂CH(CH₃)CH₃ replaces—OH, which is R¹ substituent 1 in Table A)

[0210] 2 —O—P(O)(O)—OCH₂CH₂CH₂CH₂CH₃

[0211] 3 —O—P(O)(O)—OCH₂CH₂CH₂CH₂CH₂CH₃

[0212] 4 —O—P(O)(O)—OCH₂CH₂CH(CH₂CH₂)CH₃

[0213] 5 —O—CH₂CH₂CH₂CH₂CH₂CH₃

[0214] 6 —O—C₂H₅

[0215] 7 —O—CH₂CH₂CH₃

[0216] 8 —O—CH₂CH₂CH₂CH₃

[0217] 9 —O—CH(CH₃)CHCH₃

[0218] 10 —O—C(CH₃)₃

[0219] Groups 13-1 through 13-10-6.

[0220] These groups comprise each compound named in groups 1 through10-6 where R¹ substituents 1-10 listed in Table A are replaced with thefollowing groups:

[0221] 1 —O—(CH₂)₄CH₃ (—O—(CH₂)₄CH₃ replaces —OH, which is R¹substituent 1 in Table A)

[0222] 2 —O—C(O)—NH₂

[0223] 3 —O—C(O)—NHCH₃

[0224] 4 —O—C(O)—NHC₂H₅

[0225] 5 —O—C(O)—NHCH₂CH₂CH₃

[0226] 6 —O—C(O)—NHCH₂CH₂OCH₂CH₃

[0227] 7 —O—C(O)—CH₃

[0228] 8 —O—C(O)—C₂H₅

[0229] 9 —O—C(O)—CH₂CH₂CH₃

[0230] 10 —O—C(O)—CH₂CH₂CH₂CH₃

[0231] Groups 14-1 through 14-10-6.

[0232] These groups comprise each compound named in groups 1 through10-6 where R¹ substituents 1-10 listed in Table A are replaced with thefollowing groups:

[0233] 1 —O—CH₂C₆H₅

[0234] 2 —O—CH₂C₆H₅

[0235] 3 —O—CH₂C₆H₄OCH₃

[0236] 4 —O—CH₂C₆H₄OCH₃

[0237] 5 —O—CH₂C₆H₄F

[0238] 6 —O—CH₂C₆H₄F

[0239] 7 —O—CH₂C₆H₃(OCH₃)₂

[0240] 8 —O—CH₂C₆H₃(OCH₃)₂

[0241] 9 —O—CH₂C₆H₄OCH₂CH₃

[0242] 10 —O—CH₂C₆H₄OCH₂CH₃

[0243] Groups 15-1 through 15-10-6.

[0244] These groups comprise each compound named in groups 1 through10-6 where R¹ substituents 1-10 listed in Table A are replaced with thefollowing groups:

[0245] 1 —O—C(O)—CH₂CH₂NH₂ (—O—C(O)—CH₂CH₂NH₂ replaces —OH, which is R¹substituent 1 in Table A)

[0246] 2 —O—C(O)—CH₂CH₂CH₂NH₂

[0247] 3 —O—C(O)—CH₂OH

[0248] 4 —O—C(O)—CH₂CH₂OH

[0249] 5 —O—C(O)—CH₂CH₂CH₂OH

[0250] 6 —O—C(O)—CH₂SH

[0251] 7 —O—C(O)—CH₂CH₂SH

[0252] 8 —O—C(O)—CH₂CH₂CH₂SH

[0253] 9 —O—S(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—C₂H₅

[0254] 10 —O—P(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—C₂H₅

[0255] Groups 16-1 through 16-10-6.

[0256] These groups comprise each compound named in groups 1 through10-6 where R¹ substituents 1-10 listed in Table A are replaced with thefollowing groups:

[0257] 1 —O—C(O)-A4-NH₂, where A4-NH₂ is a 4 carbon alkyl groupsubstituted with —NH₂ (—O—C(O)-A4-NH₂ replaces —OH, which is R¹substituent 1 in Table A)

[0258] 2 —O—C(O)-A6-NH₂, where A6-NH₂ is a 6 carbon alkyl groupsubstituted with —NH₂

[0259] 3 —O—C(O)-A8-NH₂, where A8-NH₂ is a 8 carbon alkyl groupsubstituted with —NH₂

[0260] 4 —O—C(O)-A4-OH, where A4-OH is a 4 carbon alkyl groupsubstituted with —OH or —O—

[0261] 5 —O—C(O)-A6-OH, where A6-OH is a 6 carbon alkyl groupsubstituted with —OH or —O—

[0262] 6 —O—C(O)-A8-OH, where A8-OH is a 8 carbon alkyl groupsubstituted with —OH or —O—

[0263] 7 —O—S(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—C₃H₇

[0264] 8 —O—P(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—C₃H₇

[0265] 9 —O—S(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—C₄H₉

[0266] 10 —O—P(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—C₄H₉

[0267] Groups 17-1 through 17-10-6.

[0268] These groups comprise each compound named in compound groups 1through 10-6 where R¹ substituents 1-10 listed in Table A are replacedwith the following groups:

[0269] 1 —O—S(O)(O)—O—CH₂—CH(O—C(O)—OH )—CH₂—O—C(O)—C₆H₁₃

[0270] 2 —O—P(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—C₆H₁₃

[0271] 3 —O—S(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—C₈H₁₇

[0272] 4 —O—P(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—C₈H₁₇

[0273] 5 —O—S(O)(O)—O—CH₂—CH(O—C(O)—OH )—CH₂—O—C(O)—CH₂C₅H₁₀OH

[0274] 6 —O—P(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—CH₂C₅H₁₀OH

[0275] 7 —O—S(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—CH₂C₃H₆OH

[0276] 8 —O—P(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—CH₂C₃H₆OH

[0277] 9 —O—S(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—CH₂C₇H₁₄OH

[0278] 10 —O—P(O)(O)—O—CH₂—CH(O—C(O)—OH)—CH₂—O—C(O)—CH₂C₇H₁₄OH

[0279] Groups 18-1 through 18-10-6.

[0280] These groups comprise each compound named in groups 1 through10-6 where R⁴ substituents 1-10 listed in Table A are replaced with thefollowing groups:

[0281] 1 —O—C(O)CH₂NH₂

[0282] 2 —O—C(O)C(CH₃)H—NH₂

[0283] 3 —O—C(O)C(CH₂C₆H₅)H—NH₂

[0284] 4 —O—C(O)—O—NHC(CH₃)H—CO₂H

[0285] 5 —O—C(O)—O—NHCH₂—CO₂H

[0286] 6 —O—C(O)—O—NH(CH₂C₆H₅)H—CO₂H

[0287] 7 —O—C(O)—CF₃

[0288] 8 —O—C(O)—CH₂CF₃

[0289] 9 —O—C(O)—(CH₂)₃CF₃

[0290] 10 —O—C(O)—(CH₂)₅CH₃

[0291] Groups 19-1 through 19-10-6.

[0292] These groups comprise each compound named in compound groups 1through 10-6 where R⁴ substituents 1-10 listed in Table A are replacedwith the following groups:

[0293] 1 —O—C(O)—O—CH₃

[0294] 2 —O—C(O)—O—CH₂CH₃

[0295] 3 —O—C(O)—O—C₃H₇

[0296] 4 —O—C(O)—O—C₄H₉

[0297] 5 —O—C(O)—O—C₆H₁₃

[0298] 6 —O—C(O)—O—C₆H₅

[0299] 7 —O—C(O)—O—C₆H₄OH

[0300] 8 —O—C(O)—O—C₆H₄OCH₃

[0301] 9 —O—C(O)—O—C₆H₄OCH₂CH₃

[0302] 10 —O—C(O)—O—C₆H₄F

[0303] Groups 20-1 through 20-10-6.

[0304] These groups comprise each compound named in groups 1 through10-6 where R⁴ substituents 1-10 listed in Table A are replaced with thefollowing groups:

[0305] 1 —O—C(O)—S—CH₃

[0306] 2 —O—C(O)—S—CH₂CH₃

[0307] 3 —O—C(O)—S—C₃H₇

[0308] 4 —O—C(O)—S—C₄H₉

[0309] 5 —O—C(O)—S—C₆H₁₃

[0310] 6 —O—C(O)—S—C₆H₅

[0311] 7 —O—C(O)—S—C₆H₄OH

[0312] 8 —O—C(O)—S—C₆H₄OCH₃

[0313] 9 —O—C(O)—S—C₆H₄OCH₂CH₃

[0314] 10 —O—C(O)—S—C₆H₄F

[0315] Groups 21-1 through 21-10-6.

[0316] These groups comprise each compound named in compound groups 1through 10-6 where R⁴ substituents 1-10 listed in Table A are replacedwith the following groups:

[0317] 1 —O—C(S)—O—CH₃

[0318] 2 —O—C(S)—O—CH₂CH₃

[0319] 3 —SH

[0320] 4 ═S

[0321] 5 —O—C(S)—O—C₆H₁₃

[0322] 6 —O—C(O)—O—CH₂C₆H₅

[0323] 7 —O—C(O)—O—CH₂C₆H₄OH

[0324] 8 —O—C(O)—O—CH₂C₆H₄OCH₃

[0325] 9 —O—C(O)—O—CH₂C₆H₄OCH₂CH₃

[0326] 10 —O—C(O)—O—CH₂C₆H₄F

[0327] Groups 22-1 through 22-10-6

[0328] These groups comprise each compound named in compound groups 1through 10-6 where R² substituents 1-10 listed in Table A are replacedwith the following groups:

[0329] 1 —O—C(S)—O—CH₃

[0330] 2 —O—C(S)—O—CH₂CH₃

[0331] 3 —O—C(S)—O—C₃H₇

[0332] 4 —O—C(S)—O—C₄H₉

[0333] 5 —O—C(S)—O—C₆H₁₃

[0334] 6 —O—C(O)—O—CH₂C₆H₅

[0335] 7 —O—C(O)—O—CH₂C₆H₄OH

[0336] 8 —O—C(O)—O—CH₂C₆H₄OCH₃

[0337] 9 —O—C(O)—O—CH₂C₆H₄OCH₂CH₃

[0338] 10 —O—C(O)—O—CH₂C₆H₄F

[0339] Groups 23-1 through 23-10-6.

[0340] These groups comprise each compound named in compound groups 1through 10-6 where R³ substituents 1-10 listed in Table A are replacedwith the following groups:

[0341] 1 —O—C(S)—O—CH₃

[0342] 2 —O—C(S)—O—CH₂CH₃

[0343] 3 —O—C(S)—O—C₃H₇

[0344] 4 —O—C(S)—O—C₄H₉

[0345] 5 —O—C(S)—O—C₆H₁₃

[0346] 6 —O—C(O)—O—CH₂C₆H₅

[0347] 7 —O—C(O)—O—CH₂C₆H₄OH

[0348] 8 —O—C(O)—O—CH₂C₆H₄OCH₃

[0349] 9 —O—C(O)—O—CH₂C₆H₄OCH₂CH₃

[0350] 10 —O—C(O)—O—CH₂C₆H₄F

[0351] Groups 24-1 through 24-10-6.

[0352] These groups comprise each compound named in compound groups 1through 10-6 where R² substituents 1-10 listed in Table A are replacedwith the following groups:

[0353] 1 —O—C(O)—O—C₆H₅

[0354] 2 —O—C(O)—O—C₆H₄OCH₃

[0355] 3 —SH

[0356] 4 ═S

[0357] 5 —O—CHR²⁴—C(O)—OR²⁵

[0358] 6 —O—CHR²⁴—C(O)—R²⁵

[0359] 7 —O—CHR²⁴—C(O)—N(R²⁵)₂

[0360] 8 —O—CHR²⁴—C(O)—NHR²⁵

[0361] 9 —O—CHR²⁴—C(O)—NH₂

[0362] 10 —O—CHR²⁴—C(O)—OC₆H₅

[0363] Groups 25-1 through 25-10-6.

[0364] These groups comprise each compound named in compound groups 1through 10-6 where R³ substituents 1-10 listed in Table A are replacedwith the following groups:

[0365] 1 —O—C(O)—O—C₆H₅

[0366] 2 —O—C(O)—O—C₆H₄OCH₃

[0367] 3 —SH

[0368] 4 ═S

[0369] 5 —O—CHR²⁴—C(O)—OR²⁵

[0370] 6 —O—CHR²⁴—C(O)—R²⁵

[0371] 7 —O—CHR²⁴—C(O)—N(R²⁵)₂

[0372] 8 —O—CHR²⁴—C(O)—NHR²⁵

[0373] 9 —O—CHR²⁴—C(O)—NH₂

[0374] 10 —O—CHR²⁴—C(O)—OC₆H₅.

[0375] Groups 26-1 through 26-25-10-6.

[0376] These groups comprise each compound named in compound groups 1through 25-10-6 wherein R⁷ in formula B is —O—, instead of —CH₂—. Thusthe 26-1 and 26-2 compounds named 1.2.5.9 have the structures

[0377] The compound group 26-8-1 and compound group 26-8-2 compoundsnamed 1.2.5.9 have the structures

[0378] The group 26-11-1 and 26-11-2 compounds named 1.2.5.9 have thestructures

[0379] Groups 27-1 through 27-25-10-6.

[0380] These groups comprise each compound named in compound groups 1through 25-10-6 wherein R⁸ in formula B is —O—, instead of —CH₂—. Thusthe 27-1 and 27-2 compounds named 1.2.5.9 have the structures

[0381] The group 27-8-1 and group 27-8-2 compounds named 1.2.5.9 havethe structures

[0382] The group 27-11-1 and 27-11-2 compounds named 1.2.5.9 have thestructures

[0383] Groups 28-1 through 28-25-10-6.

[0384] These groups comprise each compound named in compound groups 1through 25-10-6 wherein R⁹ in formula B is —O—, instead of —CH₂— and nodouble bond is present at the 1-2 position. Thus, there is, e.g., nogroup 28-3, 28-4, 28-6, 28-8-3, 28-8-4 or 28-8-6, since a 1-2 doublebond is present in these compounds and a ring oxygen at the 2 positionwould be charged. The 28-1, 28-2 and 28-5 compounds named 1.2.5.9 havethe structures

[0385] The group 28-8-1 and group 28-8-2 compounds named 1.2.5.9 havethe structures

[0386] The group 28-11-1 and 28-11-2 compounds named 1.2.5.9 have thestructures

[0387] Groups 29-1 through 29-25-10-6.

[0388] These groups comprise each compound named in compound groups 1through 25-10-6 wherein R⁷ is —NH—, instead of —CH₂—. The compounds arenamed as described for compound groups 26-1 through 26-25-10-6.

[0389] Groups 30-1 through 30-25-10-6.

[0390] These groups comprise each compound named in compound groups 1through 25-10-6 wherein R⁸ is —NH—, instead of —CH₂—. The compounds arenamed as described for compound groups 26-1 through 26-25-10-6.

[0391] Groups 31-1 through 31-25-10-6.

[0392] These groups comprise each compound named in compound groups 1through 25-10-6 wherein R⁹ is —NH—, instead of —CH₂—. and no double bondis present at the 1-2 position. Thus, there is e.g., no group 31-3,31-4, 31-6, 31-8-3, 31-8-4 or 31-8-6. The compounds are named asdescribed for compound groups 26-1 through 26-25-10-6.

[0393] Groups 32-1 through 32-25-10-6.

[0394] These groups comprise each compound named in compound groups 1through 25-10-6 wherein two of R⁷ R⁸ and R⁹ independently are —NH—, —O—or —S— instead of —CH₂—. The compounds are named as described forcompound groups 26-1 through 26-25-10-6.

[0395] Groups 33-1 through 33-25-10-6.

[0396] These groups comprise each compound named in compound groups 1through 25-10-6 wherein each of R⁷ R⁸ and R⁹ independently are —NH—, —O—or —S— instead of —CH₂—. The compounds are named as described forcompound groups 26-1 through 26-25-10-6.

[0397] Groups 34-1 through 34-25-10-6.

[0398] These groups comprise each compound named in compound groups 1through 25-10-6 wherein R⁷ is —S—, instead of —CH₂—. The compounds arenamed as described for compound groups 26-1 through 26-25-10-6.

[0399] Groups 35-1 through 35-25-10-6.

[0400] These groups comprise each compound named in compound groups 1through 25-10-6 wherein R⁸ is —S—, instead of —CH₂—. The compounds arenamed as described for compound groups 26-1 through 26-25-10-6.

[0401] Groups 36-1 through 36-25-10-6.

[0402] These groups comprise each compound named in compound groups 1through 25-10-6 wherein R⁹ is —S—, instead of —CH₂— and no double bondis present at the 1-2 position. There is, e.g., no group 36-3, 36-4,36-6, 36-8-3, 36-8-4 or 36-8-6. The compounds are named as described forcompound groups 26-1 through 26-25-10-6.

[0403] Groups 37-1 through 37-25-10-6.

[0404] These groups comprise each compound named in all of the compoundcompound groups 1 through 36-25-10-6 described above wherein R¹ is notdivalent, e.g., is not ═O, and it is in the α-configuration, instead ofthe β-configuration as shown in formula B.

[0405] Groups 38-1 through 38-25-10-6.

[0406] These groups comprise each compound named in all of the compoundgroups 1 through 36-25-10-6 described above wherein R² is not divalent,e.g., is not ═O, and it is in the α-configuration, instead of theβ-configuration as shown in formula B.

[0407] Groups 39-1 through 39-25-10-6.

[0408] These groups comprise each compound named in all of the compoundgroups 1 through 36-25-10-6 described above wherein R³ is not divalent,e.g., is not ═O, and it is in the β-configuration, instead of theα-configuration as shown in formula B.

[0409] Groups 40-1 through 40-25-10-6.

[0410] These groups comprise each compound named in all of the compoundgroups 1 through 36-25-10-6 described above wherein R⁴ is not divalent,e.g., is not ═O, and it is in the α-configuration, instead of theβ-configuration as shown in formula B.

[0411] Groups 41-1 through 41-25-10-6.

[0412] These groups comprise each compound named in all of the compoundgroups 1 through 36-25-10-6 described above wherein R² and R⁴ is notdivalent, e.g., they is not ═O, and they are both in theα-configuration, instead of the β-configuration as shown in formula B.

[0413] Groups 42-1 through 42-25-10-6.

[0414] These groups comprise each compound named in all of the compoundgroups 1 through 36-25-10-6 described above wherein, when hydrogen ispresent at the 5-position, it is in the β-configuration, instead of theα-configuration as shown in formula B.

[0415] Any of the compounds or general of compounds that are named incompound groups 1 through 42-25-10-6 are suitable for use in the methodsdescribed herein.

[0416] In some embodiments, one, or more of R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ and R¹⁸independently have the structure(s) and/or independently comprise thenamed compounds, —H, —OH, ═O, —SH, ═S, —NH₂, —CN, —N₃, halogen, ═CH₂,═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —C(O)—(CH₂)₁₋₄—CH₃, —CCH, —CCCH₃, —CH═CH₂,—CH═CH₂CH₃, —O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CH₃,—O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CF₃, —O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CH₂F,—O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CH₃, —O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CF₃,—O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CH₂F, —O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CH₃,—O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CF₃, —O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CH₂F(where m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9 or 10, usually n is 0), —CH(CH₃)—(CH₂)₂—C(O)NH—CH₂COOH,—CH(CH₃)—(CH₂)₂—C(O)NH—CH₂SO₃H, —OSi(CH₃)₂C(CH₃)₃, —C(OH)═CHCH₃,═CH(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₄CH₂F, —(CH₂)₀₋₁₄CH₂Cl, —(CH₂)₀₋₁₄CH₂Br,—(CH₂)₀₋₁₄CH₂I, —(CH₂)₂₋₁₀—O—(CH₂)₀₋₄CH₃, —(CH₂)₂₋₁₀—S—(CH₂)₀₋₄CH₃,—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄CH₃, —O—(CH₂)₀₋₁₄CH₂F, —O—(CH₂)₀₋₁₄CH₂Cl,—O—(CH₂)₀₋₁₄CH₂Br, —O—(CH₂)₀₋₁₄CH₂I, —O—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄CH₃,—O—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄CH₃, —O—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄CH₃,—O—C(O)—(CH₂)₀₋₁₄CH₂F, —O—C(O)—(CH₂)₀₋₁₄CH₂Cl, —O—C(O)—(CH₂)₀₋₁₄CH₂Br,—O—C(O)—(CH₂)₀₋₁₄CH₂I, —O—C(O)—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄CH₃,—O—C(O)—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄CH₃, —O—C(O)—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄CH₃,—O—C(S)—(CH₂)₀₋₁₄CH₂F, —O—C(S)—(CH₂)₀₋₁₄CH₂Cl, —O—C(S)—(CH₂)₀₋₁₄CH₂Br,—O—C(S)—(CH₂)₀₋₁₄CH₂I, —O—C(S)—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄CH₃,—O—C(S)—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄CH₃, —O—C(S)—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄CH₃,—(CH₂)₀₋₁₆NH₂, —(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₅CN, —(CH₂)₀₋₁₅CH═CH₂,—(CH₂)₀₋₁₅NHCH(O), —(CH₂)₀₋₁₆NH—(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₅CCH,—(CH₂)₀₋₁₅OC(O)CH₃, —(CH₂)₀₋₁₅OCH(OH)CH₃, —(CH₂)₀₋₁₅C(O)OCH₃,—(CH₂)₀₋₁₅C(O)OCH₂CH₃, —(CH₂)₀₋₁₅C(O)(CH₂)₀₋₁₅CH₃,—(CH₂)₀₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH, —O(CH₂)₁₋₁₆NH₂, —O(CH₂)₁₋₁₅CH₃,—O(CH₂)₁₋₁₅CN, —O(CH₂)₁₋₁₅CH═CH₂, —O(CH₂)₁₋₁₅NHCH(O),—O(CH₂)₁₋₁₆NH—(CH₂)₁₋₁₅CH₃, —O(CH₂)₁₋₁₅CCH, —O(CH₂)₁₋₁₅OC(O)CH₃,—O(CH₂)₁₋₁₅OCH(OH)CH₃, —O(CH₂)₁₋₁₅C(O)OCH₃, —O(CH₂)₁₋₁₅C(O)OCH₂CH₃,—O(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₃, —O(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH,—OC(O)(CH₂)₁₋₁₆NH₂, —OC(O)(CH₂)₁₋₁₅CH₃, —C(O)O(CH₂)₁₋₁₅CN,—C(O)O(CH₂)₁₋₁₅CH═CH₂, —OC(O)(CH₂)₁₋₁₅NHCH(O),—OC(O)(CH₂)₁₋₁₆NH—(CH₂)₁₋₁₅CH₃, —OC(O)(CH₂)₁₋₁₅CCH,—OC(O)(CH₂)₁₋₁₅OC(O)CH₃, —OC(O)(CH₂)₁₋₁₅OCH(OH)CH₃,—OC(O)(CH₂)₁₋₁₅C(O)OCH₃, —OC(O)(CH₂)₁₋₁₅C(O)OCH₂CH₃,—OC(O)(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₃, —OC(O)(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH,phosphoenolpyruvate, D-glucosamine, glucholic acid, glucuronic acid,pantothenic acid, pyruvic acid, glucose, fructose, mannose, sucrose,lactose, fucose, rhamnose, galactose, ribose, 2′-deoxyribose,3′-deoxyribose, glycerol, 3-phosphoglycerate, a PEG (PEG 20, PEG 100,PEG 200, PEG 10000), a polyoxyalkylene polymer, glycine, alanine,phenylalanine, threonine, proline, 4-hydroxyproline or anoligonucleotide or analog that comprises about 4 to about 21 monomers.

[0417] When a substituent is an oligonucleotide or a polymer usuallyonly a one of these is bonded to the formula 1 compound. Typically, whenR¹-R² and R⁴-R⁶ comprise one or more of these substituents (or othersdescribed herein), the substituent is present in the P-configuration,while R³ typically comprises a substituent in the β-configuration. Insome embodiments, R² is in the α-configuration.

[0418] In some embodiments, one or more of R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ and R¹⁸independently comprise a nucleoside, a nucleotide, an oligonucleotide oran analog of any of these moieties. Typically such moieties are linkedto the steroid nucleus through a terminal hydroxyl, thiol, acyl moietyor amine at the 5′, 3′ or 2′ positions, when a hydroxyl, thiol, acylmoiety or amine is present at that position. For oligonucleotides andoligonucleotide analogs, the linkage to the steroid occasionally isthrough a sugar hydroxyl at an internal 2′ position.

[0419] Analogs of phosphodiester linkages include phosphorothioatelinkages and others as described in the cited references.Oligonucleotide coupling groups means any moiety suitable for generatinga phosphodiester linkage or phosphodiester analog linkage betweenadjacent nucleotides or their analogs. Suitable oligonucleotide couplinggroups include —OH, H-phosphonate, alkylphosphonamidites orphosphoramidites such as β-cyanoethyl-phosphoramidite, N,N-diisopropylamino-β-cyanoethoxyphosphine and others as described in thecited references. Suitable purine and pyrimidine bases include adenine,guanine, cytosine, thymine, uracil and others as described in the citedreferences. Suitable nucleosides, nucleotides, oligonucleotides andtheir analogs have been described, see e.g., U.S. Pat. Nos. 4,725,677,4,973,679, 4,997,927, 4,415,732, 4,458,066, 5,047,524, 4,959,463,5,212,295, 5,386,023, 5,489,677, 5,594,121, 5,614,622, 5,624,621; andPCT publication Nos. WO 92/07864, WO 96/29337, WO 97/14706, WO 97/14709,WO 97/31009, WO 98/04585 and WO 98/04575 all of which are incorporatedherein by reference. The formula 1 compounds, e.g., those named in anyof the compound groups 1 through 42-25-10-6, are suitable for linkage tooligonucleotides modulate the lipophilicity of oligonucleotides or thetransport or permeation of an oligonucleotide into cells. Such linkagesmay be biologically labile to facilitate release of the steroid from theoligonucleotide once the conjugate has entered the cell.

[0420] Table 2 shows these and other exemplary moieties that one or moreof R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ and R¹⁸ independently can comprise. Pr means aprotecting group. These moieties are often bonded to one or more of theR¹, R² and R⁴ positions, usually to one or two of those positions. Forstructures with more than one of a given variable, e.g., X in structureA3 or A5, each is independently selected. TABLE 2

G ═CH₂

[0421] Typical containers for storage of the invention compositions andformulations will limit the amount of water that reaches the materialscontained therein. Typically, formulations are packaged in hermeticallyor induction sealed containers. The containers are usually inductionsealed. Water permeation characteristics of containers have beendescribed, e.g., Containers—Permeation, chapter, USP 23 <671>, UnitedStates Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway,Rockville, Md. 20852, pp.: 1787 et seq. (1995).

[0422] The use of formula A compounds for treatment of certain diseases,e.g., infections such as malaria, HCV or Cryptosporidium, has beendescribed. Formula A compounds have the structure

[0423] where Q₁ is —C(R₁)₂— or —C(O)—; Q₂ is —C(R₁)₂—, —C(R₁)(Y)—,—C(Y)— —CH₂—CH₂—; Q₃ is —H or —C(R₁)₃—; Q₄ is —C(R₁)₂—, —C(O)—,hydroxyvinylidine (—CH(CH═CHOH)—) or methyl methylene (—CH(CH)₃—); Q₅ is—C(R₁)₂— or —C(O)—; X and Y independently are —OH, —H, lower alkyl(e.g., C₁₋₆ alkyl), —O—C(O)—R₅, —C(O)—OR₅, halogen (i.e., —F, —Cl, —Bror —I) or ═O; each R₁ independently is —H, —F, —Cl, —Br, —I, —OH, C₁₋₆alkoxy, or C₁₋₆ alkyl; R₂ is —H, —OH, —F, —Cl, —Br, —I, C₁₋₆ alkyl, C₁₋₆alkoxy, —OR₃, an ester (e.g., —O—C(O)—R₄ or —C(O)—O—R₄), a thioester(e.g., —O—C(S)—R₄ or —C(S)—O—R₄), a thioacetal (e.g., —S—C(O)—R₄, or—C(O)—S—R₄), a sulfate ester (e.g., —O—S(O)(O)—O—R₄), a sulfonate ester(e.g., —O—S(O)—O—R₄) or a carbamate (e.g., —O—C(O)—NH—R₄ or—NH—C(O)—O—R₄) or R₂, together with the R₁ that is bonded to the samecarbon atom is ═O; R₃ is —S(O)(O)—OM,—S(O)(O)—O—CH₂—CH(O—C(O)—R₆)—CH₂—O—C(O)—R₆,—P(O)(O)—O—CH₂—CH(O—C(O)—R₇)—CH₂—O—C(O)—R₇, a glucuronide group ofstructure (B)

[0424] or R₃ is C₁₋₁₈ alkyl, C₂₋₁₈ alkenyl, C₂₋₁₈ alkynyl, a C₁₋₁₈ esteror a C₁₋₁₈ thioester, where any of the foregoing C₁₋₁₈ or C₂₋₁₈ moietiesare optionally substituted at one or more hydrogen atoms with one ormore independently selected —OR^(PR), (including —OH), —NHR^(PR),(including —NH₂) or —SR^(PR), (including —SH) groups, or R₃is a C₁₋₁₈fatty acid, C₂₋₁₀ alkynyl, (J)_(n)-phenyl-C₁₅-alkyl,(J)_(n)-phenyl-C₂₋₅-alkenyl; R₄ is —H, a protecting group, optionallysubstituted C₁₋₁₈ alkyl, optionally substituted C₁₋₁₈ alkenyl,optionally substituted C₁₋₁₈ alkynyl, optionally substituted aryl,optionally substituted aryl-C₁₋₆ alkyl, optionally substituted aryl-C₂₋₆alkenyl, optionally substituted aryl-C₂₋₆ alkynyl, optionallysubstituted heterocycle-C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl-heterocycle, optionally substituted C₂₋₆ alkynyl-heterocycle oran optionally substituted heterocycle, where any of the foregoingmoieties are optionally substituted at one, two, three, four, five ormore carbon or hydrogen atoms with one or more independently selected—O—, —S—, —NR^(PR)— (including —NH—), —NH—C(O)—, —OR^(PR) (including—OH), —NHR^(PR) (including —NH₂), —SR^(PR) (including —SH), ═O, ═S,═N—OH, —CN, —NO₂, —F, —Cl, —Br or —I groups or atoms; each R₅independently is straight or branched C₁₋₁₄ alkyl; each R₆ independentlyis straight or branched C₁₋₁₄ alkyl; each R₇ independently is straightor branched C₁₋₁₄ alkyl or a glucuronide group of structure (B); eachRPR independently is —H or an independently selected protecting group; nis 0, 1, 2 or 3; each J independently is —F, —Cl, —Br, —I, C₁₋₄ alkyl,C₁₋₄ alkenyl, C₁₋₄ alkoxy, carboxy, nitro, sulfate, sulfonyl, a C₁₋₆carboxyl ester or a C₁₋₆ sulfate ester; M is hydrogen, sodium,—S(O)(O)—O—CH₂—CH(O—C(O)—R₆)—CH₂—O—C(O)—R₆,—P(O)(O)—O—CH₂—CH(O—C(O)—R₇)—CH₂—O—C(O)—R₇ or a glucuronide group ofstructure (A); the dotted lines in formula 1 represent an optionaldouble bond, provided that there are not double bonds at both the 4-5and 5-6 positions and provided that when a double bond is present, zeroor 1 R₁ group is bonded to carbon atoms at the 1-, 2-, 4-, 5-, 6- or 17positions so that these carbon atoms are tetravalent; and the salts,stereoisomers, positional isomers, metabolites, analogs or precursors.

[0425] The formula A compounds, particularly where both R₁ at the11-position are not hydroxyl, alkoxy or a moiey that can hydrolyze to ahydroxyl, are generally suitable for use in the methods and compositionsthat are disclosed herein, e.g., their use to enhance a subject's Th1immune responses. Methods of administration and dosages are essentiallyas described herein.

[0426] Intermittent Dosing Methods.

[0427] One can intermittently administer the formula 1 compound(s),e.g., BrEA or a BrEA ester, to a subject without some of the undesiredaspects normally associated with discontinuous dosing. Such undesiredaspects include development of resistance of a pathogen (virus such asHIV or a parasite such as a Plasmodium parasite) to the therapeuticagent or failure of the patient or subject to adhere to a dosingregimen. Intermittent dosing protocols include administration of aformula 1 compound, e.g., orally, topically or parenterally as follows:(1) dosing for about 3 to about 20 days, (2) no dosing of the formula 1compound for about 4 to about 20 days, (3) dosing for about 4 to about20 days and (4) optionally repeating the dosing protocol 1, 2, 3, 4, 5,6, 10, 15, 20, 30 or more times. Often, the dosing of steps (1) and (3)will be maintained for about 3-15 days, usually about 3-5 days. Ingeneral, steps (1)-(3) of the dosing protocol recited above, will berepeated at least one time, typically at least 2, 3, 4, 5 or 6 times.For infections that tend to remain chronic, e.g., HIV, HCV or otherchronic virus or parasite infection, the intermittent dosing protocol istypically maintained over a relatively long time period, e.g., for atleast about 6 months to about 5 years.

[0428] In these intermittent dosing protocols, the formula 1 compound(s)can be administered by any suitable route, e.g., intramuscular (i.m. orI.M.), subcutaneous (s.c. or S.C.), intravenous (i.v. or I.V.),intradermal, other parenteral route, aerosol using about 0.1 to about 10mg/kg/day, usually about 0.2-4 mg/kg/day. Alternatively, one canadminister the formula 1 compound(s) orally using about 4 to about 40mg/kg/day, usually about 6-20 mg/kg/day. In some embodiments, theintermittent dosing methods exclude dosing protocols that are commonlyused to deliver contraceptive steroids to, e.g., human females, such asdaily dosing for 21 days, followed by no dosing for 7 days. In general,the non-aqueous formulations described herein that contain formula 1compound(s) are administered i.m. or s.c., while aqueous formulationsthat contain formula 1 compound(s) is administered by i.v., i.m., s.c.or other parenteral routes. The daily doses can be administered as asingle dose, especially for doses given parenterally, or the dose can besubdivided into two, three or four subdoses, usually two, especially fordoses given orally.

[0429] Exemplary embodiments are (a) administering a formula 1compound(s), e.g., BrEA or an ester or carbonate of BrEA, once everyother day for 20 days, followed by (b) no dosing for 1, 2, 3, 4, 5, 6,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 or more days and then (c)administering the formula 1 compound(s) at least once more on one day,e.g., administering the formula 1 compound(s) once every other day for20 days and (d) optionally repeating (a), (b) and (c) 1, 2, 3, 4, 5 or 6times or more. A subset of these embodiments are (a) administering aformula 1 compound(s), e.g., BrEA or an ester or carbonate of BrEA, onceevery other day for 20 days, followed by (b) no dosing for about 10-40days and then (c) administering the formula 1 compound(s) at least oncemore on one day, e.g., administering the formula 1 compound(s) onceevery other day for 20 days and (d) optionally repeating (a), (b) and(c) 1, 2, 3, 4, 5 or 6 times or more. In any of these embodiments, onecan administer the formula 1 compound(s) in 2 or 3 subdoses per day.

[0430] Other embodiments are (a) administering a formula 1 compound(s),e.g., BrEA or an ester or carbonate of BrEA, once every day for about8-12 days, followed by (b) no dosing for 1, 2, 3, 4, 5, 6, 10, 15, 20,25, 30, 35, 40, 45, 50, 55, 60 or more days and then (c) administeringthe formula 1 compound(s) at least once more on one day, e.g.,administering the formula 1 compound(s) once per day for about 8-12 daysand (d) optionally repeating (a), (b) and (c) 1, 2, 3, 4, 5 or 6 timesor more. A subset of these embodiments are (a) administering a formula 1compound(s), e.g., BrEA or an ester or carbonate of BrEA, once every dayfor about 10 days, followed by (b) no dosing for about 10-40 days andthen (c) administering the formula 1 compound(s) at least once more onone day, e.g., administering the formula 1 compound(s) once per day forabout 10 days and (d) optionally repeating (a), (b) and (c) 1, 2, 3, 4,5 or 6 times or more. In any of these embodiments, one can administerthe formula 1 compound(s) in 2 or 3 subdoses per day.

[0431] One aspect of invention intermittent dosing is monitoring thesubject's response to dosing. For example, while dosing a subject whohas a viral infection (e.g., HCV, HIV, SIV, SHIV), one can measure thesubject's or pathogen's response, e.g., amelioration of one or moresymptoms or a change in infectious particles or viral RNA in the serum.Once a response is observed dosing can be continued for one, two orthree additional days, followed by discontinuing the dosing for at leastone day (at least 24 hours), usually for at least 2 or 3 days. Once thesubject's response shows signs of remission (e.g., viral serum RNAbegins to increase), dosing can be resumed for another course. An aspectof the subject's response to formula 1 compound(s) is that the subjectmay show a measurable response within a short time, usually about 5-10days, which allows straightforward tracking of the subject's response,e.g., by monitoring viral titer in peripheral white blood cells(“PBMC”or by measuring viral nucleic acid levels in the blood. One maymonitor one or more immune cell subsets, e.g., NK, LAK, dendritic cellsor cells that mediate ADCC immune responses, during and afterintermittent dosing to monitor the subject's response and to determinewhen further administration of the formula 1 compound is indicated.These cell subsets are monitored as described herein, e.g., by flowcytometry.

[0432] For any of the treatments or methods described herein, prolongedbeneficial effects or a sustained immune response by a subject mayresult from a single administration or a few daily administrations ofthe formula 1 compound for from intermittent treatment with the formula1 compound. A single administration means that a formula 1 compound isadministered to the subject in one, two, three or more doses within a 24hour period and no further administration of any formula 1 compound tothe subject occurs for at least about 45 days to about 2 months, e.g.,for 3, 4, 5, 6 or more months. Prolonged beneficial effects or immuneresponses may also persist after a short course of treatment has beencompleted (e.g., daily dosing for 2, 3, 4, 5 or 6 days) and the subjectis no longer receiving any formula 1 compound, or, in some cases, anyother therapeutic treatment to treat the primary cause of the subject'spathological condition. Such beneficial effects can persist for morethan about 5-30 days.

[0433] In some cases, beneficial effects from treatment have beenobserved for more than 3 months (4 or 5 or more months) after a shortcourse of treatment of a subject with a formula 1 compound. Thus,administration of a formula 1 compound provides a method to effectivelyprotect a subject against progression of an infection or against adverseconsequences of unwanted immune reactions (e.g., inflammation) oragainst immunosuppression (from infection, chemotherapy, etc), withoutany dosing of the compound for at least 3 months after an initial dosingprotocol, which could be an intermittent or a continuous dosing protocolover, e.g., 1 day to about 4 months (1 -15 days, about 1 month, about 2months, etc).

[0434] Synthesis Methods.

[0435] Reagents and reaction conditions that one can use to make theformula 1 compounds have been described, see e.g., the citations above,U.S. Pat. Nos. 5,874,598, 5,874,597, 5,874,594, 5,840,900; PCTpublication number WO 9901579. General chemical synthetic methods tolink a variety of organic moieties to various reactive groups have beendescribed. For example, in G. T. Hermanson, Bioconjugate Techniques,Academic Press, 1996, functional targets such as amino acids, peptidesand carbohydrates are described at pages 3-136, while the chemistries ofreactive groups in the functional targets, e.g., amine, thiol, carboxyl,hydroxyl, aldehyde, ketone and reactive hydrogen atoms (e.g., —H linkedto an electron-donating moiety such as a heteroaryl moiety) aredescribed at pages 137-166. This reference also describes reagentsuseful to make the derivatives, e.g., zero-length cross-linkers,heterobifunctional cross-linkers, homobifunctional cross-linkers, tags,probes and polymers are described at pages 169-416 and 605-638. Thisreference also describes synthetic methods to modify oligonucleotides atpages 639-671.

[0436] In one aspect, amino acids or peptides are linked to the steroidthrough the amine group using a coupling reagent such as phosgene(Cl—CO—Cl) or Cl—CS—Cl and suitably protected amino acids or peptidesand steroids, which are protected as needed. Such linkage generates anintervening —CO—O— or a —CS—O— moiety between the amino acid or peptideand the steroid nucleus.

[0437] Exemplary Synthesis Schemes.

[0438] By way of exemplification and not limitation, the followingmethods are used to prepare the one or more of the compounds disclosedherein. Starting materials and straightforward variations of the schemesare found, e.g., in the following references, which are incorporatedherein by reference: A. P. Davis, et al., Tetrahedron Lett., 33:5111-5112, 1992; I. Takashi, el al., Chem. Pharm. Bull., 34: 1929-1933,1986; I. Weisz, et al., Arch. Pharm., 319: 952-953, 1986; T. Watabe, etal., J. Med. Chem., 13: 311-312, 1970; M. Davis, et al., J. Chem. Soc.C., (11): 1045-1052, 1967; R. C. Cambie, et al., J. Chem. Soc., PerkinTrans. 1, (20): 2250-2257, 1977; L. Minale, et al., J. Chem Soc., PerkinTrans. 1, (20): 2380-2384, 1974; C. K. Lai, et al., Steroids, 42:707-711, 1983; S. Irie, et al., Synthesis, (9): 1135-1138, 1996; E. J.Corey, J. Am. Chem. Soc., 118: 8765-8766, 1996; M. E. Annunziato, etal., Bioconjugate Chem., 4: 212-218, 1993; N. J. Cussans, et al., J.Chem. Soc., Perkin Trans. 1, (8): 1650-1653, 1980; D. H. R. Barton, etal., J. Chem. Soc., Chem. Commun., (9): 393-394, 1978; H. Loibner, etal., Helv. Chim. Acta, 59: 2100-2113, 1976; T. R. Kasturi, et al., Proc.Indian Acad. Sci., [Ser.]: Chem. Sci., 90: 281-290, 1981; T. Back, J.Org. Chem., 46: 1442-1446, 1981; A. Canovas, et al., Helv. Chim. Acta,63: 486-487, 1980; R. J. Chorvat, et al., J. Org. Chem., 43: 966-972,1978; M. Gumulka, et al., Can. J. Chem., 63: 766-772, 1985; H. Suginome,et al., J. Org. Chem., 55: 2170-2176, 1990; C. R. Engel, et al., Can.Heterocycles, 28: 905-922, 1989; H. Sugimone, et al., Bull, Chem. Soc.Jpn., 62: 193-197, 1989; V. S. Salvi, et al., Can. Steroids, 48: 47-53,1986; C. R. Engel, et al., Can. Steroids, 47: 381-399, 1986; H.Suginome, et al., Chem. Lett., (5): 783-786, 1987; T. Iwadare, et al.,J. Chem. Soc., Chem. Commun., (11): 705-706, 1985; H. Nagano, et al., J.Chem. Soc., Chem. Commun., (10): ;656-657, 1985; V. S. Salvi, et al.,Steroids, 27: 717-725, 1976; C. H. Engel, et al, Steroids, 25: 781-790,1975; M. Gobbini, et al., Steroids, 61: 572-582, 1996; A. G. Gonzalez,et al., Tetrahedron, 46: 1923-1930, 1990; S. C. Bobzin, et al., J. Org.Chem., 54: 3902-3907, 1989; B. Solaja, et al., Croat. Chem. Acta, 59:1-17, 1986; Y. Kashman, et al., Tetrahedron, 27: 3437-3445, 1971; K.Yoshida, et al., Chem. Pharm. Bull. (Tokyo), 15: 1966-1978, 1967; P. B.Sollman, etal., Chem. Commun. (11): 552-554, 1967; H. Suginome, et al.,J. Org. Chem., 55: 2170-2176, 1990; H. Suginome, et al., Journal Chem.Lett., (5): 783-786, 1987; G. A. Tolstikov, et al., Zh. Org. Khim., 22:121-132, 1986; T. Terasawa, et al., J. Chem. Soc., Perkin Trans. 1, (4):990-1003, 1979; Z. Zhuang, et al., Yougi Huaxue, (4): 281-285, 1986; W.T. Smith, et al., Trans. Ky. Acad. Sci., 45: 76-77, 1984; A. K. Batta,et al., Steroids, 64: 780-784, 1999; B. Ruan, et al., Steroids, 65:29-39, 2000; L. Garrido,et al., Steroids, 65: 85-88, 2000; P. Ramesh, etal., Steroids, 64: 785-789, 1999; M. Numazawa, et al., Steroids, 64:187-196, 1999; P. N. Rao, et al., Steroids, 64: 205-212, 1999; M.Numazawa, et al., Steroids, 64: 320-327, 1999; U.S. Pat. Nos. 3,281,431,3,301,872, 3,325,535, 3,325,536, 3,952,018, 4,602,008, 5,571,795,5,627,270, 5,681,964, 5,744,453; international publication numbers WO9408588, WO 9508558, WO 9508559, WO 9638466, WO 9809450; United Kingdompatent numbers GB 1168227, GB 813529, GB 802618; French patent number824529; Japan patent number JP 45010134; European patent applications EP232788, EP 430078; and German patent number DE 19631189.

[0439] Scheme 1.

[0440] For the structures shown in scheme 1, R⁵—R⁹ are as defined forformula 1 compounds. Thus, when R⁵ and R⁶ are both —CH₃ in theα-configuration, R⁷, R⁸ and R⁹ are all —CH₂—, H at the 9 and 14positions are in the α-configuration, acetate at the 3-position is inthe β-configuration, and H at the 8 position is in the β-configuration,the first compound in scheme 1 is DHEA acetate. The acetate groups atthe 3, 7, 16, 17 or other positions in this scheme and in other schemesdisclosed herein may independently be other ester moieties as describedherein, e.g., C₂₋₅₀ esters including —C(O)—(CH₂)₀₋₄—(CF₂)₀₋₄—CF₃,including —C(O)—CF₃, —C(O)—C₂₋₂₉ optionally substituted alkyl,—C(O)—CH₂—C₂₋₂₈ optionally substituted alkenyl, —C(O)—CH₂—C₂₋₂₈optionally substituted alkynyl, —C(O)—(CH₂)₀₋₆-optionally substitutedphenyl, or —C(O)—(CH₂)₀₋₆-optionally substituted heterocycle or otherorganic moieties as disclosed herein or in the cited references.

[0441] Typical substituents for these organic moieties are as describedherein, including one, two, three or more independently selected —O—,═O, optionally protected hydroxyl, —S—, optionally protected thiol,—NH—, optionally protected —NH₂, optionally protected —C(O)OH,—C(O)—NH—, —C(O)—NH₂, —NH₂—C(O)—H, —NH₂—C(O)—C₀₋₄H₁₋₉,—NH₂—C(O)—O—CO₀₋₄H₁₋₉, —CN, —NO₂, —N₃ or halogen. Reactive groups areprotected as needed, e.g., ═O would usually be protected in the LiCRreaction that is used to generate compound 1 in scheme 1 below.

[0442] Scheme 2.

[0443] Compounds of formula 2 are prepared from structure A compoundsshown in scheme 1 using the last two steps of Scheme 1: (1) dibromantin,(2) LiBr, (3) Li—C—R, where R is CR^(A) and RA is —H or —C₁₋₁₂optionally substituted alkyl. When R⁷, R⁸ and R⁹ are all —CH₂—, H at the9 and 14 positions are in the α-configuration and H at the 8 position isin the β-configuration the first compound in scheme 1 is DHEA acetate.Typical substituents for the RA alkyl moiety includes one, two or moreindependently selected —O—, optionally protected ═O, optionallyprotected hydroxyl, —S—, optionally protected thiol, —NH—, optionallyprotected —NH₂, optionally protected —C(O)OH, —C(O)—NH—, —C(O)—NH₂,—NH₂—C(O)—H, —NH₂—C(O)—C₀₋₄H₁₋₉, —NH₂—C(O)—O—C₀₋₄H₁₋₉, —CN, —NO₂, —N₃ orhalogen.

[0444] Scheme 3.

[0445] The allylic bromination at C-7 is done as in Scheme 1. R andR^(A) are as defined in Schemes 1 and 2.

[0446] Scheme 4.

[0447] The addition of lithium reagent (lithium acetylide when R is —CH)to the 17-position >C═O in the presence of the bromide at C-1 6 resultsin epoxide formation or in a pinacol rearrangement. Alternatively,compounds without of structure 3 can be dehydrated by mild acidcatalysis to form compounds of formula 4 by treatment of the alkene withBr₂, H₂O. R and R^(A) are as defined in Schemes 1 and 2.

[0448] Scheme 5.

[0449] Sodium borohydride gives a mixture of epimers at C-7, which maybe separated by standard methods, e.g., HPLC, TLC or columnchromatography. To obtain the pure 7α-OH compound, allylic brominationfollowed by hydrolysis is accomplished as described in Schemes 1 and 3.

[0450] Scheme 6.

[0451] Formula 6 compounds are prepared by treatment of the acetate withlithium acetylide as in Schemes 1, 2, 3 or 4. R and R^(A) are as definedin Schemes 1 and 2.

[0452] Scheme 7.

[0453] Formula 7 compounds are prepared from the 3-acetate with reagentsdescribed in Schemes 1 and 4. R and R^(A) are as defined in Schemes 1and 2.

[0454] Scheme 8.

[0455] Formula 8 compounds are prepared from the formula A compounds bysodium borohydride reduction at C-17 followed by acetylation.

[0456] Scheme 9.

[0457] The starting material is made using reactions described inSchemes 1 and 3.

[0458] Scheme 10.

[0459] Reduction and acetylation at C-3 and hydrolysis and oxidation atC-1 7 will allow formula 10a and 10b compounds to undergofunctionalization as shown in Schemes 1-9 at C-3, C-16 and C-1 7. The7-oxo acetate can be substituted for the formula A compound 3-acetateand functionalization at C-3, C-16 and C-17 is achieved similarly for7-oxo compounds using the reactions shown in schemes 1-9.

[0460] Treatment of 10a with LDA, followed by alkylation of the enolateallows introduction of side chains such as R¹⁰, whiich may be, e.g.,C1-C20 alkyl (methyl, ethyl), C1-C20 alkenyl (CH₂═CH—(CH₂)₀₋₆—), benzyl,—(CH₂)₁₋₄—O—(CH₂)₀₋₄—CH₃.

[0461] Schemes 1-9 show the introduction of the hydroxyl function at thepositions shown. Methods to convert hydroxyl to other functional groupsare accomplished essentially as described, e.g., in the references citedherein. For example, esters, of formula 1-10c compounds, such as—O—C(O)—R^(B) where R^(B) is a C₁₋₅₀ organic moiety, are prepared fromthe steroid alcohol by treatment with the appropriate acid anhydride oracid chloride (R^(B)—C(O)—Cl) to form any desired ester. Ethers, such as—O—R^(B), are prepared from alcohols by formation of the alkaline metalalkoxide (Na⁺ or K⁺) followed by treatment with a primary or secondaryiodide (R^(B)—I). Thionoesters, R^(B)—C(S)—O—, are prepared by treatingthe R^(B)—C(O)—O— ester with Lawesson's reagent.

[0462] Sulfates, NaO—S(O)(O)—O—, R^(B)—O—S(O)(O)—O—, e.g.,CH₃(CH₂)₀₋₁₈—S(O)(O)—O—, are prepared by treatment of alcohols withchlorosulfonic acid followed by NaOH or alternatively by oxidation ofsulfites using KMnO₄. If the alkyl (e.g., methyl) ester is desiredalkylchloro-sulfonate (methylchloro-sulfonate) can be used. SulfitesHO—S(O)—O— and ammonium salts NH₄ O—S(O)—O, or R^(B) O—S(O)—O— esters(e.g., CH₃ O—S(O)—O—) are prepared by standard methods. The ammoniumsalts are prepared by treatment of alcohols with ammonia and sulfurdioxide. The esters such as alkyl, alkenyl and alkynyl esters (e.g.,methyl ester) are obtained when alcohols are treated withalkylchlorosulfite (e.g., methycholorosulfite), alkenylchlorosulfite oralkynylchlorosulfite in the presence of a suitable base such astriethylamine. Phosphoesters, R^(B)O—P(OR^(PR))(O)—O— are prepared bytreating the alcohol with diethylchlorophosphate in the presence ofNa₂CO₃. Alternatively, if the alcohol is treated with phosphoric aciddiesters in the presence of triphenylphospine (PPh₃) anddiethylazodicaboxylate (DEAD) the corresponding triesters are formedwith inversion (Mitsunobu reaction).

[0463] Phosphothioesters, R^(B)O—P(SR^(PR))(O)—O— are generated bytreatment of alcohols with the monothio analog of diethylchlorophosphateas described for phosphoesters yielding the phosphothioesters.Carbonates, R^(B)O—C(O)—O— are generated from the corresponding steroidalcohol using the chloroformate (R^(B)—C(O)—Cl), e.g., C₁₋₂₀ alkyl,alkenyl or alkynyl chloroformates (e.g. CH₃(CH₂)₀₋₅—C(O)Cl). Carbamates,R^(B)—NH—C(O)—O— are made from steroid alcohols by treatment withisocyanates (R^(B)N═C═O) or NaOCN in the presence of trifluroroaceticacid. Aminoacid esters, ZNX—CHY—C(O)—O— are generated by coupling thesteroid alcohol with the acid chloride of the N-protected amino acid.

[0464] Oxidation of hydroxyl groups that are linked to the steroidnucleus is used to obtain ketones and related functionalities. Forexample, conversion of alcohols to ketones can be achieved using avariety of oxidizing agents such as CrO₃ in AcOH, or pyridiniumcholorchromate, pyridinium dichromate or oxalyl chloride withtriethylamine (Swern oxidation). Thioketones (═S) are prepared bytreating ketones with Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide;commercially available from Aldrich). Thioacetals, —C(SR^(B))(SR^(B))—,are prepared from ketones (—C(O)—) by treatment with R^(B)—SH thiolsunder acid catalysis conditions (e.g., HCl). Phosphonoesters,RO—P(OR^(PR))(O)—, are generated by addition of the phosphorus aciddiester to ketones in the presence of KF to yield hydroxyphosphonoesters. One may optionally remove the hydroxy group using adehydration and hydrogenation sequence.

[0465] Substitution of hydroxyl groups is used to generate a number offunctionalities. For example, thiols, —SH, are prepared from alcohols byconversion of the alcohol with inversion to the bromide using PBr₃.Treatment of the bromide with thiourea followed by NaOH gives the thiol.Thioethers, R^(B)—S—, are prepared from thiols by treatment with NaOHand the required halide, e.g., alkyl halide. Alternatively, alcoholderivatives like tosylates or mesylates can be displaced by thiolateanions, R^(B)—S^(—), to yield the thioether. Thioesters, R—C(O)—S—, areprepared by treating the tosylate (mesylate) of the alcohol with thesodium salt of the thioacid.

[0466] Substitution of hydroxyl groups can be used to generate bothesters, R^(B)O—C(O)—, and amides, NHR^(B)—C(O)—, linked to the steroidat carbon atoms. For amides and amines, R^(B) is —H, a protecting groupor a C₁₋₅₀ organic moiety. These are synthesized from the steroidbromide with inversion by displacement with NaCN. The cyanide group canbe hydrolyzed to the amide or the acid. The acid is esterified ortreated by standard peptide coupling reactions with an O-protected aminoacid in the presence of a suitable carboxyl activating agents such asdicyclohexylcarbodiimide (DCC) to form steroid —C(O)—NH—CHY—C(O)—OR,where Y is the side chain of an amino acid or a C1-C10 organic moietyand R is a protecting group (or hydrogen when deprotected).

[0467] Amines and derivatives of amines, e.g., R^(B)NH—, R^(B)—C(O)NH—,R^(B)OC(O)—NH— or R^(B)O—C(O)—CHR^(B)—NH— linked to steroid carbonatoms, are typically prepared by standard methods. For example, amines(NH₂-steroid) are generally prepared using the Hoffmann rearrangement(Br₂, NaOH) from the amide (NH₂—C(O)-steroid) or the Curtiusrearrangement (NaN₃) from the acid chloride of the steroid. The R^(B)substituent can subsequently be introduced by alkylation. Steroidalcohols can be used as starting materials under standard Mitsunobuconditions (PPh₃, DEAD) to yield N-Boc sulfonamides usingN-(t-butoxycarbonyl)-p-toluenesulfonamide. One can selectively removeeither protecting group. Treatment with trifluoroacetic acid affords thesulfonamide (R^(B)—S(O)(O)—NH-steroid). Alternatively, sodiumnapthalenide deprotects to give the N-Boc compound. Amines (NH₂-steroid)can be converted to amides (R^(B)NH—C(O)-steroid) using acyl chlorides(R^(B)—C(O)—Cl). Treatment with ethyl chloroformate gives theN-carbamate (R^(B)O—C(O)—NH-steroid). The amine (NH₂-steroid) can bealkylated with an α-bromoester (R^(B)—C(O)—CHY—NH₂) to yield the amioacid substituted steroid (R^(B)—O—C(O)—CHY—NH-steroid).

[0468] Where reactions such as substitutions give a product mixture, thedesired intermediate is optionally separated from other products or atleast partially enriched (e.g., enriched at least about 10-fold, usuallyat least about 50-1 00-fold) from other products before subsequentreactions are conducted. Substitution at steroid carbon atoms willgenerally proceed with greatest efficiency at the 3-position, which isrelatively sterically unhindered and C-17 is generally somewhat lessaccessible than the C-3 position. The relative reactivities of the C-3,C-7, C-17 and C-16 positions allow one to use their reactivities tocontrol the sequential introduction of different functional groups intothe same steroid molecule. Also, groups, such as hydroxyl at morereactive positions, C-3 or C-1 7, may be sequentially protected ordeprotected to allow introduction of functional groups at otherpositions, such as C-7 or C-16.

[0469] Polymers such as PEG are linked to the compounds essentially asdescribed above. For example, PEG200 or PEG300 is linked to the steroidat the 3, 7, 16, 17 or other positions by an ether linkage(PEG-O-steroid) using a PEG alkoxide (PEG-ONa), to displace the steroidbromide. Alternatively, PEG-Br can be treated with the steroid alkoxide.Polyethylene glycol esters such as those described in U.S. Pat. No.5,681,964 can also be prepared using a suitable formula 1 compound andthe methods described therein. Monosaccharides or polysaccharides andoligonucleotides are linked to steroid hydroxyl groups using knownmethods, see e.g., U.S. Pat. No. 5,627,270.

[0470] Formula 1 steroid analogs that comprise one or more ringheteroatoms are synthesized according to the following methods.

[0471] Scheme 11.

[0472] Formula 1 compounds that comprise two or three ring heteroatomsare prepared as shown in the schemes. In the scheme, X is —CH₂—, —NH—,—O—, or —S—; R⁴⁰ is —H or —Br; R⁴¹ is an organic moiety having about 12carbon atoms or less, typically C1-C8 optionally substituted alkyl(e.g., methyl, hydroxymethyl, ethyl, propyl) or C2- C8 optionallysubstituted alkenyl having a single double bond (e.g., vinyl) with 1, 2,3 or more indepenently selected substituents (e.g., —OH, —COOH, —O—) andwith any substituents that comprise a functional group generally beingprotected. Preparation of compound 20 from 19 is accomplished using aglycol such as HOC(CH₃)₂C(CH₃)₂OH in acid (H⁺) (B. H. Lipshutz et al.,Synth. Commun. 12: 267, 1982). The use of a bulky protecting groupfacilitates generation of a double bond at the 5-6 position over the 4-5position.

[0473] Schemes 12A-12D.

[0474] Compounds of structure 12 are generated as shown in the schemesbelow. Most of the reactions are conducted essentially as described. Seee.g., W. D. Langley, Org. Syn. 1, 122, 1932 (compound 30); R. Ratcliffeet al., J. Org. Chem. 35: 4000, 1970 (compound 32); A. I. Meyers et al.,J. Org. Chem. 39: 2787, 1974 (compound 33, 41); J. L. Isidor et al., J.Org. Chem. 38: 544, 1973 (compound 35); G. Wittig et al., Chem. Ber. 87:1318, 1954 (compound 36); P. M. Pojer et al., Tet. Lett. 3067, 1976(compound 38); A. Maercker, Org. React. 14: 270, 1965 (compound 37); E.J. Corey et al., Tet. Lett. 3269 1975 (compound 37); R. S. Tipson, J.Org. Chem. 9: 235, 1944 (compound 39); G. W. Kabalka, J. Org. Chem. 51:2386, 1986; B. B. Carson et al., Org. Synth. 1: 179, 1941 (compound 43);H. J. Bestman et al., Justus Liebigs Ann. Chem. 693: 132 1966 (compound39); M. Miyano et al., J. Org. Chem. 37: 268, 1972 (compound 51); W. H.Glaze et al., J. Org. Chem. 33: 1987, 1968 (compound 52).

[0475] Compounds of structure 12 where X is NH, S and CH₂ are preparedas shown in schemes 12B, 12C and 12D respectively.

[0476] Scheme 13.

[0477] The scheme and reactions shown below are used to prepare thecompound of structure 13 and related compounds that are used tointroduce oxygen, carbon, nitrogen or sulfur into the R⁷ and R⁸positions of formula 1 compounds. The reactant in the preparation ofcompound 63, 3-chloro-2-methylpropene (reg. No. 563-47-3), is availablecommercially (e.g., Aldrich, Fluka).

[0478] Compound 59 and analogs of compound 59 where CH₂, S or NH CH₂replaces oxygen are prepared as shown in the following reactions.Conditions suitable for conversion of compound 106 to 107 have beendescribed (T. Hamada et al., Heterocycles 12: 647, 1979; T. Hamada etal., J. Am. Chem. Soc. 108: 140, 1986).

[0479] Conversion of the methyl ketone (—C(O)—CH₃) moiety in compoundshaving the structure

[0480] (R—C(O)—CH₃) to other functionalities is accomplished as follows.The methyl ketone is cleaved to yield a carboxyl moiety using, e.g., Br₂or I₂ in base, followed by treatment with acid (H₃O⁺) essentially asdescribed (S. J. Chakrabarty Oxidations in Organic Chemistry Part C, W.Trahnnousy, editor, Academic Press, NY, 1987, chapter 5; L. J. Smith etal., Org. Synth. III 302, 1953), to yield R—C(O)—OH. The carboxylic acidis reduced to the alcohol using LiAlH₄. Conversion of the carboxylicacid to the bromide is accomplished using, e.g., Br₂ in water,essentially as described (J. S. Meck et al., Org. Synth. V, 126, 1973;A. Mckillop et al., J. Org. Chem. 34: 1172, 1969).

[0481] Compounds of structure 11 are brominated using N-bromosuccinimideto obtain steroids and analogs with bromine at the 7-position.

[0482] The 11A compounds are deprotected to yield the aldehyde compounds12. As shown in scheme 11, the bromine atom is ultimately found at the7-position. The bromine may be converted to a hydroxyl by reaction ofthe steroid with base (e.g., aqueous KOH), and the hydroxyl may in turnbe protected using known methods, e.g., using C₆H₅—CH₂—Br and base(KOH). The alcohol is protected and deprotected essentially usingdescribed methods, see, e.g., W. H. Hartung et al., Org. React. 7: 263,1953; E. J. Rerst et al., J. Org. Chem. 29: 3725, 1968; A. M. Felix etal., J. Org. Chem. 43: 4194, 1978; D. A. Evans et al., J. Am. Chem. Soc.101: 6789, 1979; international publication number WO 98/02450. Similarreactions are used to convert a bromine at other positions to ahydroxyl. Other substituents are linked to the steroids as described inschemes 1 -10.

[0483] Alternative routes to introduce a functional group into the7-position are also suitable. For example, formula 1 compounds that havea double bond at the 5-6 position and are unsubstituted at the7-position are optionally protected, e.g., hydroxyl groups are protectedwith acetate, and a ketone is introduced into the 7-position byoxidation with chromic acid essentially as described (U.S. Pat. No.2,170,124). The carbonyl (═O) at 7 is reduced to a hydroxyl using mildconditions, e.g., AI(Oi—Pr)₃, to avoid reducing the 5-6 double bond. Theuse of stronger reducing conditions, e.g., reduction with LiBH₄ in THF,leads to conversion of the 7-carbonyl to hydroxyl and to reduction ofthe 5-6 double bond and other double bonds that may be present in themolecule.

[0484] Selective hydrogenation of a double bond at the 16-17 positionwithout reduction of a double bond at 5-6 is accomplished using H₂ andPd. In general, ketones (═O) can be protected using a glycol, e.g.,reaction with ethylene glycol in p-toluenesulfonic acid and benzene,before subsequent oxidation or reduction reactions are conducted.

[0485] Various groups that may comprise the formula 1 compoundsdescribed herein, e.g., hydroxyl groups or ketones bonded to the steroidnucleus, or substituted alkyl groups, substituted heterocycles, aminoacids and peptides, can contain one or more reactive moieties such ashydroxyl, carboxyl, amino or thiol. Intermediates used to make formula 1compounds may be protected as is apparent in the art. Noncyclic andcyclic protecting groups and corresponding cleavage reactions aredescribed in “Protective Groups in Organic Chemistry”, Theodora W.Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6)(hereafter “Greene”) and will not be detailed here. In the context ofthe present invention, these protecting groups are groups that can beremoved from the molecule of the invention without irreversibly changingthe covalent bond structure or oxidation/reduction state of theremainder of the molecule. For example, the protecting group, —R^(PR),that is bonded to an —O— or —NH— group can be removed to form —OH or—NH₂, respectively, without affecting other covalent bonds in themolecule. At times, when desired, more than one protecting group can beremoved at a time, or they can be removed sequentially. In compounds ofthe invention containing more than one protecting group, the protectinggroups are the same or different.

[0486] Protecting groups are removed by known procedures, although itwill be understood that the protected intermediates fall within thescope of this invention. The removal of the protecting group may bearduous or straightforward, depending upon the economics and nature ofthe conversions involved. In general, one will use a protecting groupwith exocyclic amines or with carboxyl groups during synthesis of aformula 1 compound. For most therapeutic applications amine groupsshould be deprotected. Protecting groups commonly are employed toprotect against covalent modification of a sensitive group in reactionssuch as alkylation or acylation. Ordinarily, protecting groups areremoved by, e.g. hydrolysis, elimination or aminolysis. Thus, simplefunctional considerations will suffice to guide the selection of areversible or an irreversible protecting group at a given locus on theinvention compounds. Suitable protecting groups and criteria for theirselection are described in T. W. Greene and P. G. M. Wuts, Eds.“Protective Groups in Organic Synthesis” 2nd edition, Wiley Press, atpps. 10-142, 143-174, 175-223, 224-276, 277-308, 309-405 and 406-454.

[0487] Determination of whether a group is a protecting group is made inthe conventional manner, e.g., as illustrated by Kocienski, Philip J.;“Protecting Groups” (Georg Thieme Verlag Stuttgart, New York, 1994)(hereafter “Kocienski”), Section 1.1, page 2, and Greene Chapter 1,pages 1-9. In particular, a group is a protecting group if when, basedon mole ratio, 90% of that protecting group has been removed by adeprotection reaction, no more than 50%, typically 25%, more typically10%, of the deprotected product molecules of the invention haveundergone changes to their covalent bond structure oroxidation/reduction state other than those occasioned by the removal ofthe protecting group. When multiple protecting groups of the same typeare present in the molecule, the mole ratios are determined when all ofthe groups of that type are removed. When multiple protecting groups ofdifferent types are present in the molecule, each type of protectinggroup is treated (and the mole ratios are determined) independently ortogether with others depending on whether the deprotection reactionconditions pertinent to one type are also pertinent to the other typespresent. In one embodiment of the invention, a group is a protectinggroup if when, based on mole ratio determined by conventionaltechniques, 90% of that protecting group has been removed by aconventional deprotection reaction, no more than 50%, typically 25%,more typically 10%, of the deprotected product molecules of theinvention have undergone irreversible changes to their covalent bondstructure or oxidation/reduction state other than those occasioned bythe removal of the protecting group. Irreversible changes requirechemical reactions (beyond those resulting from aqueous hydrolysis,acid/base neutralization or conventional separation, isolation orpurification) to restore the covalent bond structure oroxidation/reduction state of the deprotected molecule of the invention.

[0488] Protecting groups are also described in detail together withgeneral concepts and specific strategies for their use in Kocienski,Philip J.; “Protecting Groups” (Georg Thieme Verlag Stuttgart, New York,1994), which is incorporated by reference in its entirety herein. Inparticular Chapter 1, Protecting Groups: An Overview, pages 1-20,Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, DiolProtecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups,pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184,Chapter 6, Amino Protecting Groups, pages 185-243, Chapter 7, Epilog,pages 244-252, and Index, pages 253-260, are incorporated withspecificity in the context of their contents. More particularly,Sections 2.3 Silyl Ethers, 2.4 Alkyl Ethers, 2.5 Alkoxyalkyl Ethers(Acetals), 2.6 Reviews (hydroxy and thiol protecting groups), 3.2Acetals, 3.3 Silylene Derivatives, 3.41,1,3,3-Tetraisopropyldisiloxanylidene Derivatives, 3.5 Reviews (diolprotecting groups), 4.2 Esters, 4.3 2,6,7-Trioxabicyclo[2.2.2]octanes[OBO] and Other Ortho Esters, 4.4 Oxazolines, 4.5 Reviews (carboxylprotecting groups), 5.2 O,O-Acetals, 5.3 S,S-Acetals, 5.4 O,S-Acetals,5.5 Reviews (carbonyl protecting groups), 6.2 N-Acyl Derivatives, 6.3N-Sulfonyl Derivatives, 6.4 N-Sulfenyl Derivatives, 6.5 N-AlkylDerivatives, 6.6 N-Silyl Derivatives, 6.7 Imine Derivatives, and 6.8Reviews (amino protecting groups), are each incorporated withspecificity where protection/deprotection of the requisitefunctionalities is discussed. Further still, the tables “Index to thePrincipal Protecting Groups” appearing on the inside front cover andfacing page, “Abbreviations” at page xiv, and “reagents and Solvents” atpage xv are each incorporated in their entirety herein at this location.

[0489] Typical hydroxy protecting groups are described in Greene atpages 14-118 and include Ethers (Methyl); Substituted Methyl Ethers(Methoxymethyl, Methylthiomethyl, t-Butylthiomethyl,(Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl,p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl,t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl,2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl,Bis(2-chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl,Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-Methoxytetrahydrothiopyranyl, 4-MethoxytetrahydropthiopyranylS,S-Dioxido, 1-[(2-Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl);Substituted Ethyl Ethers (1-Ethoxyethyl, 1-(2-Chloroethoxy)ethyl,1-Methyl-1-methoxyethyl, 1-Methyl-1-benzyloxyethyl,1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-Trichloroethyl,2-Trimethylsilylethyl, 2-(Phenylselenyl)ethyl, t-Butyl, Allyl,p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl); SubstitutedBenzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl,p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p-Cyanobenzyl,p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-Oxido,Diphenylmethyl, p, p′-Dinitrobenzhydryl, 5-Dibenzosuberyl,Triphenylmethyl, alpha-Naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl,Tri(p-methoxyphenyl)methyl, 4-(4′-Bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-Tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-Tris(levulinoyloxyphenyl)methyl,4,4′,4″-Tris(benzoyloxyphenyl)methyl,3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-Bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-Anthryl,9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,1,3-Benzodithiolan-2-yl, Benzisothiazolyl, S,S-Dioxido); Silyl Ethers(Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,Dimethylisopropylsilyl, Diethylisopropylsily, Dimethylthexylsilyl,t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl,Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl,t-Butylmethoxyphenylsilyl); Esters (Formate, Benzoylformate, Acetate,Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate,Methoxyacetate, Triphenyl-methoxyacetate, Phenoxyacetate,p-Chlorophenoxyacetate, p-poly-Phenylacetate, 3-Phenylpropionate,4-Oxopentanoate (Levulinate), 4,4-(Ethylenedithio)pentanoate, Pivaloate,Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,2,4,6-Trimethylbenzoate (Mesitoate); Carbonates (Methyl,9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl,2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl, Vinyl,Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl,o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl Thiocarbonate,4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate); Groups With AssistedCleavage (2-Iodobenzoate, 4-Azidobutyrate, 4-Nitro-4-methylpentanoate,o-(Dibromomethyl)benzoate, 2-Formyl benzenesulfonate,2-(Methylthiomethoxy)ethyl Carbonate, 4-(Methylthiomethoxy)butyrate,2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters(2,6-Dichloro-4-methylphenoxyacetate,2,6-Dichloro-4-(1,1,3,3-tetramethyl-butyl)phenoxyacetate,2,4-Bis(1,1-dimethylpropyl)phenoxyacetate, Chorodiphenylacetate,Isobutyrate, Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate),o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, α-Naphthoate, Nitrate,Alkyl N,N,N′, N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate,Borate, Dimethylphosphinothioyl, 2,4-Dinitro-phenylsulfenate); andSulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate,Tosylate (Tos)).

[0490] More typically hydroxy protecting groups include subtitutedmethyl ethers, substituted benzyl ethers, silyl ethers, and estersincluding sulfonic acid esters, still more typically, trialkylsilylethers, tosylates and acetates.

[0491] Typical 1,2- and 1,3-diol protecting groups are described inGreene at pages 118-142 and include Cyclic Acetals and Ketals(Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene,(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene,Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,alpha-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative,alpha-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene);and Silyl Derivatives (Di-t-butylsilylene Group,1,3-(1,1,3,3-Tetraiso-propyldisiloxanylidene) Derivative,Tetra-t-butoxydisiloxane-1,3-diylidene Derivative, Cyclic Carbonates,Cyclic Boronates, Ethyl Boronate, Phenyl Boronate).

[0492] More typically, 1,2- and 1,3-diol protecting groups includeepoxides and acetonides.

[0493] Typical amino protecting groups are described in Greene at pages315-385 and include Carbamates (Methyl and Ethyl, 9-Fluorenylmethyl,9(2-Sulfo)fluoroenylmethyl, 9-(2,7-Dibromo)fluorenylmethyl,2,7-Di-t-buthyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]-methyl, 4-Methoxy-phenacyl); Substituted Ethyl (2,2,2-Trichoroethyl,2-Trimethylsilylethyl, 2-Phenylethyl, 1-(1-Adamantyl)-1-methylethyl,1,1-Dimethyl-2-haloethyl, 1,1-Dimethyl-2,2-dibromoethyl,1,1-Dimethyl-2,2,2-trichloroethyl, 1-Methyl-1-(4-biphenylyl)ethyl,1-(3,5-Di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-Pyridyl)ethyl,2-(N,N-Dicyclohexylcarboxamido)ethyl, t-Butyl, 1-Adamantyl, Vinyl,Allyl, 1-Isopropylallyl, Cinnamyl, 4-Nitrocinnamyl, 8-Quinolyl,N-Hydroxypiperidinyl, Alkyldithio, Benzyl, p-Methoxybenzyl,p-Nitrobenzyl, p-Bromobenzyl, p-Chorobenzyl, 2,4-Dichlorobenzyl,4-Methylsulfinylbenzyl, 9-Anthrylmethyl, Diphenylmethyl); Groups WithAssisted Cleavage (2-Methylthioethyl, 2-Methylsulfonylethyl,2-(p-Toluenesu Ifonyl )ethyl, [2-(1,3-Dithianyl)]methyl,4-Methylthiophenyl, 2,4-Dimethylthiophenyl, 2-Phosphonioethyl,2-Triphenylphosphonioisopropyl, 1,1-Dimethyl-2-cyanoethyl,m-Choro-p-acyloxybenzyl, p-(Dihydroxyboryl)benzyl,5-Benzisoxazolylmethyl, 2-(Trifluoromethyl)-6-chromonylmethyl); GroupsCapable of Photolytic Cleavage (m-Nitrophenyl, 3,5-Dimethoxybenzyl,o-Nitrobenzyl, 3 ,4-Dimethoxy-6-nitrobenzyl,Phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives(Phenothiazinyl-(10)-carbonyl Derivative,N′-p-Toluenesulfonylaminocarbonyl, N′-Phenylaminothiocarbonyl);Miscellaneous Carbamates (t-Amyl, S-Benzyl Thiocarbamate, p-Cyanobenzyl,Cyclobutyl, Cyclohexyl, Cyclopentyl, Cyclopropylmethyl,p-Decyloxybenzyl, Diisopropyl methyl, 2,2-Dimethoxycarbonylvinyl,o-(N,N-Dimethyl-carboxamido)benzyl,1,1-Dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-Dimethylpropynyl,Di(2-pyridyl)methyl, 2-Furanylmethyl, 2-Iodoethyl, Isobornyl, Isobutyl,Isonicotinyl, p-(p′-Methoxyphenylazo)benzyl, 1-Methylcyclobutyl,1-Methylcyclohexyl, 1-Methyl-1-cyclopropylmethyl,1-Methyl-1-(3,5-dimethoxyphenyl)ethyl,1-Methyl-1-(p-phenylazophenyl)ethyl, 1-Methyl-1-phenylethyl,1-Methyl-1-(4-pyridyl)ethyl, Phenyl, p-(Phenylazo)-benzyl,2,4,6-Tri-t-butylphenyl, 4-(Trimethylammonium)benzyl,2,4,6-Trimethylbenzyl); Amides (N-Formyl, N-Acetyl, N-Choroacetyl,N-Trichoroacetyl, N-Trifluoroacetyl, N-Phenylacetyl,N-3-Phenylpropionyl, N-Picolinoyl, N-3-Pyridylcarboxamide,N-Benzoylphenylalanyl Derivative, N-Benzoyl, N-p-Phenylbenzoyl); AmidesWith Assisted Cleavage (N-o-Nitrophenylacetyl, N-o-Nitrophenoxyacetyl,N-Acetoacetyl, (N′-Dithiobenzyloxycarbonylamino)acetyl,N-3-(p-Hydroxyphenyl)propionyl, N-3-(o-Nitrophenyl)propionyl,N-2-Methyl-2-(o-nitrophenoxy)propionyl,N-2-Methyl-2-(o-phenylazophenoxy)propionyl, N-4-Chlorobutyryl,N-3-Methyl-3-nitrobutyryl, N-o-Nitrocinnamoyl, N-AcetylmethionineDerivative, N-o-Nitrobenzoyl, N-o-(Benzoyloxymethyl)benzoyl,4,5-Diphenyl-3-oxazolin-2-one); Cyclic Imide Derivatives (N-Phthalimide,N-Dithiasuccinoyl, N-2,3-Diphenylmaleoyl, N-2,5-Dimethylpyrrolyl,N-1,1,4,4-Tetramethyl-disilylazacyclopentane Adduct, 5-Substituted1,3-Dimethyl-1,3,5-triazacyclo-hexan-2-one, 5-Substituted1,3-Dibenzyl-1,3,5-triazacyclohexan-2-one, 1-Substituted3,5-Dinitro-4-pyridonyl); N-Alkyl and N-Aryl Amines (N-Methyl, N-Allyl,N-[2-(Trimethylsilyl)ethoxy]methyl, N-3-Acetoxypropyl,N-(1-Isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary AmmoniumSalts, N-Benzyl, N-Di(4-methoxyphenyl)methyl, N-5-Dibenzosuberyl,N-Triphenylmethyl, N-(4-Methoxyphenyl)diphenylmethyl,N-9-Phenylfluorenyl, N-2,7-Dichloro-9-fluorenylmethylene,N-Ferrocenylmethyl, N-2-Picolylamine N′-Oxide); Imine Derivatives(N-1,1-Dimethylthiomethylene, N-Benzylidene, N-p-methoxybenylidene,N-Diphenylmethylene, N-[(2-Pyridyl)mesityl]methylene,N,(N′,N′-Dimethylaminomethylene, N,N′-Isopropylidene,N-p-Nitrobenzylidene, N-Salicylidene, N-5-Chlorosalicylidene,N-(5-Chloro-2-hydroxyphenyl)phenylmethylene, N-Cyclohexylidene); EnamineDerivative (N-(5,5-Dimethyl-3-oxo-1-cyclohexenyl)); N-Metal Derivatives(N-Borane Derivatives, N-Diphenylborinic Acid Derivative,N-[Phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, N-Copper orN-Zinc Chelate); N-N Derivatives (N-Nitro, N-Nitroso, N-Oxide); N-PDerivatives (N-Diphenylphosphinyl, N-Dimethylthiophosphinyl,N-Diphenylthiophosphinyl, N-Dialkyl Phosphoryl, N-Dibenzyl Phosphoryl,N-Diphenyl Phosphoryl); N-Si Derivatives; N-S Derivatives; N-SulfenylDerivatives (N-Benzenesulfenyl, N-o-Nitrobenzenesulfenyl,N-2,4-Dinitrobenzenesulfenyl, N-Pentachlorobenzenesulfenyl,N-2-nitro-4-methoxybenzenesulfenyl, N-Triphenylmethylsulfenyl,N-3-Nitropyridinesulfenyl); and N-Sulfonyl Derivatives(N-p-Toluenesulfonyl, N-Benzenesulfonyl,N-2,3,6-Trimethyl-4-methoxybenzenesulfonyl,N-2,4,6-Trimethoxybenzenesulfonyl,N-2,6-Dimethyl-4-methoxybenzenesulfonyl, N-Pentamethylbenzenesulfonyl,N-2,3,5,6,-Tetramethyl-4-methoxybenzenesulfonyl,N-4-methoxybenzenesulfonyl, N-2,4,6-Trimethylbenzenesulfonyl,N-2,6-Dimethoxy-4-methylbenzenesulfonyl,N-2,2,5,7,8-Pentamethylchroman-6-sulfonyl, N-Methanesulfonyl,N-.beta.-Trimethylsilyethanesulfonyl, N-9-Anthracenesulfonyl, N-4-(4′,8′-Dimethoxynaphthylmethyl)benzenesulfonyl, N-Benzylsulfonyl,N-Trifluoromethylsulfonyl, N-Phenacylsulfonyl).

[0494] More typically, amino protecting groups include carbamates andamides, still more typically, N-acetyl groups.

[0495] Groups capable of biological cleavage typically include prodrugs.A large number of such groups are described in “Design of Prodrugs”,Hans Bundgaard (Elsevier, N.Y., 1985, ISBN 0-444-80675-X) (Bundgaard)and will not be detailed here. In particular, Bundgaard, at pages 1-92,describes prodrugs and their biological cleavage reactions for a numberof functional group types. Prodrugs for carboxyl and hydroxyl groups aredetailed in Bundgaard at pages 3 to 10, for amides, imides and otherNH-acidic compounds at pages 10 to 27, amines at pages 27 to 43, andcyclic prodrugs at pages 62 to 70. These moieties are optionally bondedto the steroid at one two or more of R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ and R¹⁸.

[0496] Metabolites.

[0497] Also falling within the scope of this invention are the in vivometabolites of the compounds described herein, to the extent suchproducts are novel and unobvious over the prior art. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered formula 1 compound, dueto enzymatic or chemical processes. Accordingly, the invention includesnovel and unobvious compounds produced by a process comprisingcontacting a compound of this invention with a subject, e.g., a human,rodent or a primate, for a period of time sufficient to yield ametabolic product thereof. Such products typically are identified bypreparing a radiolabeled (e.g. ¹⁴C,³H, ¹³¹I, ³²P, ³⁵S or ⁹⁹Tc) compoundof the invention, administering it parenterally in a detectable dose(e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse,guinea pig, primate, or to a human, allowing sufficient time formetabolism to occur (typically about 30 seconds to 30 hours) andisolating its conversion products from the urine, blood or otherbiological samples. These products are easily isolated since they arelabeled (others are isolated by the use of antibodies capable of bindingepitopes surviving in the metabolite). The metabolite structures aredetermined in conventional fashion, e.g. by MS, HPLC or NMR analysis. Ingeneral, analysis of metabolites is done in the same way as conventionaldrug metabolism studies well-known to those skilled in the art. Theconversion products, so long as they are not otherwise found in vivo,are useful in diagnostic assays for therapeutic dosing of the compoundsof the invention even if they possess no therapeutic activity of theirown.

[0498] Formulations and Compositions for Preparing Formulations.

[0499] While it is possible for the active ingredient(s) to beadministered alone it is usual to present them as pharmaceuticalformulations. The formulations, both for veterinary and for human use,of the invention comprise at least one active ingredient, i.e., aformula 1 compound, together with one or more acceptable excipientstherefor and optionally other therapeutic ingredients.

[0500] Another aspect of the invention relates to compositionscomprising one or more pharmaceutically acceptable excipients orcarriers. One or more formula 1 compound(s) (also referred to as the“active ingredient(s)”) are administered by any route appropriate to thecondition to be treated. Suitable routes for the non-aqueous liquidformulations and other formula 1 compound formulations include oral,rectal, nasal, topical (including buccal and sublingual), vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural). In general, the non-aqueousliquid formulations are delivered by a parenteral route. In otherembodiments, such as the invention intermittent dosing methods, theformula 1 compound(s) may be present as a non-aqueous liquidformulation, a dry solid formulation that is an oral, topical,parenteral formulation, or as an aqueous liquid formulation that is usedparenterally, orally or topically. It will be appreciated that thepreferred route may vary with, for example, the subject's pathologicalcondition or weight or the subject's response to therapy with a formula1 compound or other therapy appropriate to the circumstances.

[0501] The formulations include those suitable for the foregoingadministration routes. The formulations may conveniently be presented inunit dosage form and may be prepared by any of the methods well known inthe art of pharmacy. Techniques, excipients and formulations generallyare found in, e.g., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa. 1985, 17^(th) edition, Nema et al., PDA J. Pharm. Sci.Tech. 1997 51:166-171. Methods to make invention formulations includethe step of bringing into association an active ingredient(s) with theexcipient(s). In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidexcipients or finely divided solid excipients or both, and then, ifappropriate, shaping the product.

[0502] Formulations of the invention suitable for oral administrationare prepared as discrete units such as capsules, cachets or tablets eachcontaining a predetermined amount of the active ingredient; as a powderor granules; as solution or a suspension in an aqueous liquid or anon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient(s) may also bepresented as a bolus, electuary or paste.

[0503] A tablet is made by compression or molding, optionally with oneor more accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient(s) in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered active ingredient(s) moistened with aninert liquid diluent. The tablets may optionally be coated or scored andoptionally are formulated so as to provide slow or controlled release ofthe active ingredient(s) therefrom.

[0504] For infections of the eye or other external tissues e.g. mouthand skin, the formulations are typically applied as a topical ointmentor cream containing the active ingredient(s) in an amount of, forexample, 0.075 to 20% w/w (including active ingredient(s) in a rangebetween 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7%w/w, etc.), often 0.2 to 15% w/w and most often 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

[0505] If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound that enhances absorption or penetration ofthe active ingredient(s) through the skin or other affected areas.Examples of such dermal penetration enhancers include dimethylsulphoxide and related analogs.

[0506] The oily phase of the emulsions of this invention may beconstituted from known excipients in a known manner. While the phase maycomprise merely an emulsifier (otherwise known as an emulgent), itdesirably comprises a mixture of at least one emulsifier with a fat oran oil or with both a fat and an oil. A hydrophilic emulsifier may beincluded together with a lipophilic emulsifier, which acts as astabilizer. Some embodiments include both an oil and a fat. Together,the emulsifier(s) with or without stabilizer(s) make up the so-calledemulsifying wax, and the wax together with the oil and fat make up theso-called emulsifying ointment base which forms the oily dispersed phaseof the cream formulations.

[0507] Emulgents and emulsion stabilizers suitable for use in theformulation of the invention include Tween60™, Span80™, cetostearylalcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate andsodium lauryl sulfate.

[0508] The choice of suitable oils or fats for the formulation is basedon achieving the desired cosmetic properties. Creams are generally anon-greasy, non-staining and washable products with suitable consistencyto avoid leakage from tubes or other containers. Straight or branchedchain, mono- or dibasic alkyl esters such as di-isoadipate, isocetylstearate, propylene glycol diester of coconut fatty acids, isopropylmyristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used. These may be used alone or in combinationdepending on the properties required. Alternatively, high melting pointlipids such as white soft paraffin and/or liquid paraffin or othermineral oils are used.

[0509] Formulations suitable for topical administration to the eye alsoinclude eye drops wherein the active ingredient(s) is dissolved orsuspended in a suitable excipient(s), especially an aqueous solvent foractive ingredient(s) that comprise one or more charges at pH values nearneutrality, e.g., about pH 6-8. The active ingredient(s) is typicallypresent in such formulations in a concentration of about 0.5-20% w/w,typically about 1 -10% w/w, often about 2-5% w/w.

[0510] Formulations suitable for topical administration in the mouthinclude lozenges comprising the active ingredient in a flavored basis,usually sucrose and acacia or tragacanth; pastilles comprising theactive ingredient(s) in an inert basis such as gelatin and glycerin, orsucrose and acacia; and mouthwashes comprising the active ingredient ina suitable liquid excipient(s).

[0511] Formulations for rectal administration may be presented as asuppository with a suitable base comprising for example cocoa butter ora salicylate.

[0512] Formulations suitable for intrapulmonary or nasal administrationhave a particle size for example in the range of 0.01 to 500 microns(including average particle sizes in a range between 0.01 and 500microns in 0.1 micron or other increments, e.g., 0.05, 0.1, 0.5, 1, 1.5,2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6, 7, 8, 9, 10, 20, 25, 30, 35, 50,75, 100, etc. microns), which is administered by rapid inhalationthrough the nasal passage or by inhalation through the mouth so as toreach the alveolar sacs. Suitable micronized formulations includeaqueous or oily solutions or suspensions of the active ingredient(s).Formulations suitable for aerosol, dry powder or tablet administrationmay be prepared according to conventional methods and may be deliveredwith other therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis of viral or other infections as describedherein. Such formulation may be administered, e.g., orally, parenterally(i.v., i.m., s.c.), topically or by a buccal route.

[0513] Formulations suitable for vaginal administration may be presentedas pessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient(s) such excipients asare known in the art to be appropriate.

[0514] Formulations suitable for parenteral administration includeaqueous and non-aqueous sterile injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents.

[0515] The formulations are presented in unit-dose or multi-dosecontainers, for example sealed ampules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid excipient, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Unit dosage formulations are those containing adaily dose or unit daily sub-dose, as recited herein, or an appropriatefraction thereof, of the active ingredient(s).

[0516] It should be understood that in addition to the ingredientsparticularly mentioned above the formulations of this invention mayinclude other agents or excipients conventional in the art having regardto the type of formulation in question, for example those suitable fororal administration may include flavoring agents.

[0517] The invention further provides veterinary compositions comprisingat least one active ingredient as above defined together with aveterinary excipient(s) therefor. Veterinary excipients are materialsuseful for the purpose of administering the composition and may besolid, liquid or gaseous materials that are otherwise inert oracceptable in the veterinary art and are compatible with the activeingredient(s). These veterinary compositions may be administered orally,parenterally or by any other desired route.

[0518] Invention formulations include controlled release pharmaceuticalformulations containing an active ingredient(s) (“controlled releaseformulations”) in which the release of the active ingredient(s) iscontrolled and regulated to allow less frequency dosing or to improvethe pharmacokinetic or toxicity profile of a given active ingredient(s).

[0519] An effective dose of active ingredient(s) depends at least on thenature of the condition being treated, toxicity, whether the compound(s)is being used prophylactically (lower doses) or against an activeinfection or condition, the method of delivery, and the pharmaceuticalformulation, and will be determined by the clinician using conventionaldose escalation studies. It can be expected to be from about 0.05 toabout 30 mg/kg body weight per day. For example, for topical deliverythe daily candidate dose for an adult human of approximately 70 kg bodyweight will range from about 1 mg to about 500 mg, generally betweenabout 5 mg and about 40 mg, and may take the form of single or multipledoses or administration sites.

[0520] Embodiments include formulations that comprise a liposome orlipid complex that comprises a formula 1 compound(s), e.g., BrEA or anester, carbamate, carbonate, amino acid or peptide thereof. Suchformulations are prepared according to known methods, e.g., U.S. Pat.Nos. 4,427,649, 5,043,165, 5,714,163, 5,744,158, 5,783,211, 5,795,589,5,795,987, 5,798,348, 5,811,118, 5,820,848, 5,834,016 and 5,882,678. Theliposomes optionally contain an additional therapeutic agent(s), e.g.,amphotericin B, cis-platin, adriamycin, a protease inhibitor, anucleoside or a nucleotide analog, such as one of those mentionedherein. Formulations that comprise liposomes can be delivered to asubject by any standard route, e.g., oral, aerosol or parenteral (e.g.,s.c., i.v. or i.m.).

[0521] Therapeutic Applications.

[0522] The formula 1 compounds, or the biologically active substancesproduced from these compounds by hydrolysis or metabolism in vivo, havea number of clinical and non-clinical applications. The compounds aregenerally useful to enhance Th1 immune responses or to reduce Th2 immuneresponses. As used herein, reference to Th1 or Th2 immune responsesmeans such responses as observed in mammals generally and not asobserved in the murine system, from which the Th1 and Th2 terminologyoriginated. Thus, in humans, Th1 cells preferentially display chemokinereceptors CXCR3 and CCR5, while Th2 cells preferentially express theCCR4 molecule and a smaller amount of the CCR3 molecule.

[0523] Aspects of the invention include compositions that comprise anamount of at least one formula 1 compound effective to enhance therelative proportion of a desired immune cell subset, e.g., CD4⁺ T cells,NK cells or dendritic cells, or to modulate one or more functions ofimmune cell subsets and a pharmaceutically acceptable carrier. Typicalimmune modulation centers on modulating expression of gene(s) thatenhance of Th1 immune responses or reduces of Th2 immune responses.Functions that the formula 1 compounds affected include expression of CDmolecules or alteration of the proportion of cell subsets, e.g., CD4⁺ orCD8⁺ T cells, or their relative numbers in a subject's blood or tissues.CD molecules participate in the function of various immune cell subsetsand can be useful as markers for immune function in vivo. In someaspects, the formula 1 compounds activate immune cells which generallyalters (increases or decreases) expression of, or changes the numbers ofcells that express combinations of, CD4, CD6, CD8, CD25, CD27, CD28,CD30, CD38, CD39, CD43, CD45RA, CD45RO, CD62L, CD69, CD71, CD90 orHLA-DR molecules. Often, the numbers of cells that express thesemolecules are increased, e.g., CD25, CD16 or CD69. Typically suchincreases are observed as an increased proportion of circulating whiteblood cells that express one or more of these molecules. In some casesthe number of such molecules per cell is detectably altered.

[0524] Expression of one or more adhesion molecules CD2, CD5, CD8,CD11a, CD11b, CD11c, CD18, CD29, CD31, CD44, CD49a, CD49b, CD49c, CD49d,CD49e, CD49f, CD50, CD54, CD58, CD1 03 or CD104 are also detectablyaffected after administration of the formula 1 compounds to a subject.Often, the numbers of cells that express these molecules are increased,e.g., CD5 or CD56. The adhesion molecules function in various aspects ofimmune responses, such as binding to class I MHC molecules, transducingsignals between cells or binding to molecules in the extracellularmatrix associated with endothelial or other cell types. Administrationof the formula 1 compounds to a subject also affects the numbers ofcertain immune cell subsets, e.g., NK cells (e.g., CD8⁻, CD56⁺ or CD8⁺,CD56⁺) or lymphokine activated killer cells (LAK). Increased circulatingNK or LAK cells are typically observed, which is reflected in increasednumbers of cells that express one or more of CD16, CD38, CD56, CD57 orCD94. Also, increased numbers of circulating dendritic cell precursorsare observed, as shown by increases in cells that express one or more ofCD1 1 c, CD80, CD83, CD106 or CD123. Although one can observe anincreased proportion of circulating white blood cells that express oneor more of these molecules, in some instances the number of suchmolecules per cell is detectably altered. Both the cell numbers and thedensity of CD molecule per cell can also be detectably modulated.Modulation of immune cell subsets typically occurs on intermittentdosing of a formula 1 compound.

[0525] Expression of one or more homing receptors such as CD62L is mayalso be detectably affected after administration of the formula 1compounds to a subject. Often, the numbers of cells that express thesemolecules are increased, e.g., CD62L.

[0526] Other CD molecules that are modulated by the presence of theformula 1 compounds in a subject include cytokine receptor moleculessuch as CD115, CDW116, CD117, CD118, CDW119, CD120a, CD120b, CD121a,CD121b, CD122, CD123, CD124, CD125 CD126, CDW127, CDW128 or CDW130.Often, the numbers of receptor molecules per cell will be modulated. Forexample, receptors for cytokines that mediate Th1 immune responses(e.g., IL-2, γIFN) will typically increase in or on cells that mediateTh1 immune responses. Modulation of these molecules may be by directinteractions with a receptor(s) in the cell that expresses the cytokinereceptor or indirectly by modulation of cytokine synthesis in theaffected cells or in other cells, typically immune cells, that mayinteract with the cells whose receptor synthesis is being modulated.

[0527] Treatment of a subject with a formula 1 compound can result in achange of at least 25-50% above or below (e.g., at least 30% or at least40% above or below) the control or basal level of some immune cellsubsets. For example, increases of more than about 30% in the totalnumbers of activated CD8⁺ T cells, e.g., CD8⁺, CD69⁺, CD25⁺ T cells,CD8⁺, CD69⁺, CD25⁺ T cells or CD8⁺, CD69⁻, CD25⁺ T cells, usually occursby 7 days after a single dose of a formula 1 compound to a subject. Suchincreases may be greater than 50%, 60% or 100% in the total numbers ofactivated CD8⁺ T cells or subsets of activated CD8⁺ T cells inindividual subjects. Typically such increases are about in the totalnumbers of activated CD8⁺ T cells or subsets of activated CD8⁺ T cellsaverages about 30-40%, with individual subjects experiencing increasesover 100% in the numbers of activated CD8⁺ T cells per unit blood volumecompared to the basal level.

[0528] Administration of the formula 1 compounds can affect other immunecell subsets. For example, the concentration of circulating CD4⁺, CD69⁺,CD25⁻ (Th1 helper cells) and CD8⁺, CD16⁺, CD38⁺ LAK cells or CD8⁻,CD16⁺, CD38⁺ LAK cells typically increases during or after the course ofdosing a subject with a formula 1 compound. Also, CD8⁻, CD16⁺, CD38⁺ andCD8⁺, CD16⁺, CD38⁺ (ADCC effector cells) and low side scatter Lin⁻, DR⁺,CD123⁺ (dendritic precursors) or low side scatter Lin⁻, DR⁺, CD11c⁺(dendritic cells or precursors) may show modest to significantincreases.

[0529] In subjects that are immunosuppressed, e.g., from infection(e.g., viral (HIV, HCV), bacterial infection or parasite infection) orfrom chemotherapy (e.g., an antiviral therapy, a cancer chemotherapy ora radiation therapy), administration of the formula 1 compounds to thesubject results in a favorable shift in the balance of Th1 or Th2responses the subject can mount in the face of immunosuppression. WhenTh1 responses are suboptimal or insufficient, treatment with a formula 1compound results in enhancement of Th1 responses or a reduction in Th2responses. Conversely, when Th2 responses are suboptimal orinsufficient, treatment with a formula 1 compound results in enhancementof Th2 responses or a reduction in Th1 responses. The formula 1compounds can thus be used to shift the nature of a subject's immuneresponse to result in a more balanced immune response fromimmunosuppression. Alternatively, the compounds can selectively suppressinappropriate or unwanted immune responses. Enhanced Th1 responsesappears to be at least partly due to one or more of (i) a reduction inbiological restraints, e.g., high levels of IL-4 or IL-10, on Th1functions by preexisting primed Th1 effector cells, (ii) enhanceddifferentiation of Th0 cells to Th1 cells or enhanced responses mediatedby Th1 cells, (iii) enhanced function of accessory cell function, e.g.,antigen presentation by dendritic precursor cells or by macrophages,(iv) enhanced proliferation and differentiation of Th1 precursor orprogenitor cells, (v) enhanced IL-12 expression in dendritic cells ortheir precursors, which results in enhanced differentiation of Th1 cellsfrom Th0 precursors, (vi) enhanced expression or activity of factorsassociated with Th1 functions, e.g., IL-2, gamma interferon (γIFN) orlymphotoxin.

[0530] An aspect of the invention methods is an alteration in theexpression of IL-4 or IL-10 that occurs after administration of aformula 1 compound, e.g., BrEA, to a subject. A consistent observationis that extracellular IL-4 or IL-10 levels rapidly decrease to levelsthat are undetectable by ELISA. Intracellular IL-10 levels are reducedto levels that are near or below the limits of detection by flowcytometry. The administration of a formula 1 compound to a subject thusprovides a means to inhibit either or both of these interleukins. Suchinhibition may be associated with enhancement of Th1 immune responsesrelative to Th2 or Th0 responses, e.g., in subjects where Th1 responsesare suppressed (e.g., from viral, bacterial or parasite infection (HIV,HCV, etc) or chemotherapy) or are otherwise suboptimal. In manysubjects, levels of either IL-4 or IL-10, usually IL-10, before dosingwith a formula 1 compound is low or undetectable. In these subjects,dosing with the formula 1 compound results in a rapid drop in theinterleukin that is detectable, usually IL-4.

[0531] In some embodiments, the formula 1 compound(s) is administered toa subject who has a pathogen infection, such as a viral, bacterial orparasite infection. The formula 1 compounds can be considered for use ina broad scope of infections (see, e.g., J. B. Peter, editor, Use andInterpretation of Laboratory Tests in Infectious Disease, 5^(th)edition, Specialty Laboratories, Santa Monica, Calif. 90404, 1998, pages1-271), since the compounds generally enhance Th1 immune responsesand/or reduce Th2 immune responses. Difficulty in treating someinfections, e.g., progressive toxoplasmic encephalitis, malaria,tuberculosis, leishmaniasis and schistosomiasis, often appear to beassociated with unwanted Th2 immune responses. Typically unwanted Th2immune responses are associated with, or caused by, increased expressionof one or more cytokines or interleukins such as IL-4 and IL-10.Administration of a formula 1 compound, or other compounds disclosedherein, will generally reduce the expression of one or more of theTh2-associated cytokines or interleukins. At the same time, thecompounds enhance the expression of one or more cytokines orinterleukins associated with Th1 immune responses. Because of theircapacity to modulate Th1 and Th2 immune responses, the compounds areuseful for a variety of clinical conditions, e.g., infection,immunosuppression or cancer, where an enhanced Th1 immune response isdesired. For example, in disseminated or diffuse tuberculosis, a reducedTh2 response would be desirable to allow a patient to slow progressionof the disease or to clear infected cells more efficiently.

[0532] An aspect of the invention provides embodiments where a formula 1compound and a glutathione reductase inhibitor such as buthathionesulfoximine [CH₃—(CH₂)₃—S(═O)(═NH)—(CH₂)₂—CHNH₂—C(O)—OH] areadministered to a subject to treat infections, e.g., a parasiteinfection such as malaria, Toxoplasma, Cryptosporidium, or to treat acancer or malignancy. The decreased supply of reduced glutathione mayenhance phagocytosis by macrophage, possibly due to enhanced oxidativedamage in infected cells or in replicating malignant cells.Alternatively, the use of a glutathione reductase inhibitor may resultin improved recognition of infected or malignant cells by the immunesystem. A formula 1 compound, such as BrEA, and buthathione sulfoximineare used, e.g., to enhance clearance of ring stage malaria from infectedcells or to enhance immune system recognition of malignant cellscompared to the use of the formula 1 compound alone. The infections andmalignancies where these embodiments apply are as described herein.

[0533] Another aspect of the invention provides for the use of a formula1 compound and a flavonoid, e.g., a naragin flavonoid, to enhance thebioavailability of the formula 1 compound. In these embodiments, the aneffective amount of a flavonoid is administered to a subject who isreceiving a formula 1 compound. Typically about 1-10 mg of flavonoid perkg of body weight is administered to the subject a flavonoid such asbavachinin A, didymin (isosakuranetin-7-rutinoside or neoponcirin),flavanomarein (isookanine-7-glucoside), flavanone azine, flavanonediacetylhydrazone, flavanone hydrazone, silybin, silychristin,isosilybin or silandrin. The flavonoid compound is typicallyadministered with the formula 1 compound or a few hours, e.g., about 1,2 or 3 hours, before the formula 1 compound is administered to thesubject.

[0534] Liposome formulations can be used to enhance delivery of theformula 1 compound(s) to certain cell types such as tumor cells (seee.g., U.S. Pat. No. 5,714,163) or to cells of the reticuloendothelialsystem (“RES”). The RES includes macrophages, mononuclear phagocyticcells, cells lining the sinusoids of the spleen, lymph nodes, and bonemarrow, and the fibroblastic reticular cells of hematopoietic tissues.In general, RES cells are phagocytic and they are targets for targeteddelivery of a formula 1 compound(s) in vitro or in vivo using liposomes,or other compositions or formulations. Thus, one can deliver formula 1compound to a neoplasm that is derived from reticuloendothelial tissue(reticuloendothelioma). The liposomes may also optionally comprise apeptide from an infectious agent such as a malaria parasite. Thepeptides may facilitate the generation of a MHC class II and B cellresponse.

[0535] Vaccine Adjuvants.

[0536] The compounds disclosed herein may also be used as vaccineadjuvants with immunogens or components of immunogenic compositions toprepare antibodies capable of binding specifically to the formula 1compounds, their metabolic products which retain immunologicallyrecognized epitopes (sites of antibody binding) or to standard antigensthat are used for vaccination against, e.g., infectious agents ormalignant cells. The immunogenic compositions therefore are useful asintermediates in the preparation of antibodies that bind to formula 1compounds for use, e.g., in diagnostic, quality control, or the like,methods or in assays for the compounds or their novel metabolicproducts. In addition, the compounds are useful for raising antibodiesagainst otherwise non-immunogenic polypeptides, in that the compoundsmay serve as haptenic sites stimulating an immune response.

[0537] The hydrolysis products of interest include products of thehydrolysis of the protected acidic and basic groups discussed above. Insome embodiments the acidic or basic amides comprising immunogenicpolypeptides such as albumin, keyhole limpet hemocyamin and othersdescribed below generally are useful as immunogens. The metabolicproducts described above may retain a substantial degree ofimmunological cross reactivity with the compounds of the invention.Thus, the antibodies of this invention will be capable of binding to theunprotected compounds of the invention without binding to the protectedcompounds; alternatively the metabolic products, will be capable ofbinding to the protected compounds and/or the metabolic products withoutbinding to the protected compounds of the invention, or will be capableof binding specifically to any one or all three. The antibodiesdesirably will not substantially cross-react with naturally-occurringmaterials. Substantial cross-reactivity is reactivity under specificassay conditions for specific analytes sufficient to interfere with theassay results.

[0538] The immunogens of this invention contain the compound of thisinvention presenting the desired epitope in association with animmunogenic substance. Within the context of the invention suchassociation means covalent bonding to form an immunogenic conjugate(when applicable) or a mixture of non-covalently bonded materials, or acombination of the above. Immunogenic substances include adjuvants suchas Freund's adjuvant, immunogenic proteins such as viral, bacterial,yeast, plant and animal polypeptides, in particular keyhole limpethemocyanin, serum albumin, bovine thyroglobulin or soybean trypsininhibitor, and immunogenic polysaccharides. Typically, the compoundhaving the structure of the desired epitope is covalently conjugated toan immunogenic polypeptide or polysaccharide by the use of apolyfunctional (ordinarily bifunctional) cross-linking agent. Methodsfor the manufacture of hapten immunogens are conventional per se. Any ofthe methods used heretofore for conjugating haptens to immunogenicpolypeptides or the like are suitably used here, taking into account thefunctional groups on the precursors or hydrolytic products which areavailable for cross-linking and the likelihood of producing antibodiesspecific to the epitope in question as opposed to the immunogenicsubstance.

[0539] Typically the polypeptide is conjugated to a site on the compoundof the invention distant from the epitope to be recognized.

[0540] The conjugates are prepared in conventional fashion. For example,the cross-linking agents N-hydroxysuccinimide, succinic anhydride orC₂₋₈ alkyl—N═C═N—C₂₋₈ alkyl are useful in preparing the conjugates ofthis invention. The conjugates comprise a compound of the inventionattached by a bond or a linking group of 1-100, typically, 1-25, moretypically about 1-10 carbon atoms to the immunogenic substance. Theconjugates are separated from starting materials and by products usingchromatography or the like, and then are sterile filtered and vialed forstorage. Synthetic methods to prepare hapten-carrier immunogens havebeen described, see, e.g., G. T. Hermanson, Bioconjugate TechniquesAcademic Press, 1996, pages 419-493.

[0541] The compounds of this invention are cross-linked for examplethrough any one or more of the following groups: a hydroxyl group, acarboxyl group, a carbon atom, or an amine group. Included within suchcompounds are amides of polypeptides where the polypeptide serves as anabove-described protecting group.

[0542] Animals are typically immunized against the immunogenicconjugates or derivatives and antisera or monoclonal antibodies preparedin conventional fashion.

[0543] In embodiments where the formula 1 compounds are used asadjuvants to enhance a subject's immune response to antigens such asproteins, peptides or virus or cell preparations, the formula 1 compoundis administered at about the same time that the antigen is delivered tothe subject, e.g., within about 7 days of when the antigen isadministered to the subject. In some embodiments, the formula 1 compoundis administered 1, 2, 3 or 4 days before the antigen is administered tothe subject. In other embodiments, the formula 1 compound isadministered on the same day that the antigen is administered to thesubject. In additional embodiments, the formula 1 compound isadministered 1, 2 or 3 days after the antigen is administered. Theformula 1 compound can be administered to the subject using any of theformulations or delivery methods described herein or in the referencescited herein. Aspects of the invention include compositions orformulations that comprise a formula 1 compound, one or more excipientsand an antigen or antigen preparation such as disrupted cells or virusesor such as attenuated viruses or a DNA vaccine.

[0544] Related embodiments include a method comprising administering toa subject (e.g., a mammal such as a human or a primate), or deliveringto the subject's tissues, an effective amount of a formula I compoundand a specific antigen. These methods are useful to enhance thesubject's immune response to the antigen. Immune responses that areenhanced include a mucosal immune response to an antigen such as aprotein, peptide, polysaccharide, microorganism, tumor cell extract orlethally radiated tumor or pathogen cells (e.g., antigens or cells frommelanoma, renal cell carcinoma, breast cancer, prostate cancer, benignprostatic hyperplasia, virus or bacteria, or other tumor or pathogen asdisclosed herein). Aspects of these embodiments include enhancement ofthe subject's immune response when an antigen or immunogen isadministered intranasally or orally. In these aspects, the formula 1compound is administered about simultaneously with the antigen or withinabout 3-72 hours of antigen administration. The use of immune modulatingagents to enhance immune responses to a vaccine has been described,e.g., U.S. Pat. No. 5,518,725.

[0545] Other uses for the formula 1 compound(s) include administeringthe compound(s) to a subject who suffers from a pathologicalcondition(s). The treatment may treat or ameliorate the source of thecondition(s) and/or symptoms associated with the pathologicalcondition(s) such as infection with a pathogen(s) (viruses, bacteria,fungi), a malignancy, unwanted immune response, i.e., an immune responsethat causes pathology and/or symptoms, e.g., autoimmune conditions orallergy or conditions such as hypoproliferation conditions, e.g., normalor impaired tissue growth, or wound healing or burn healing, or inimmunosuppression conditions, e.g., conditions characterized by anabsence of a desired response and/or an inadequate degree of a desiredresponse.

[0546] Many cancers or malignancies are associated with an unwanted Th2immune response or a deficient Th1 response. An insufficient Th1 immuneresponse may play a role in the capacity of malignant cells to escapeimmune surveillance. These conditions include non-small cell lungcancer, bronchogenic carcinoma, renal cell cancer or carcinoma,lymphoma, glioma, melanoma, pancreatic or gastric adenocarcinoma, humanpappilomavirus associated cervical intraepithelial neoplasia, cervicalcarcinoma, hepatoma and cutaneous T-cell lymphoma (mycosis fungoides,Sezary syndrome).

[0547] In some of these embodiments, the subject's hyperproliferation ormalignant condition may be associated with one or more pathogens. Forexample hepatocellular carcinoma associated with HCV or HBV, Kaposi'ssarcoma associated with HIV-1 or HIV-2, T cell leukemia associated withHTLV I, Burkitt's lymphoma associated with Epstein-Barr virus orpapillomas or carcinoma associated with papilloma viruses (HPV 6, HPV11, HPV 16, HPV 18, HPV 31, HPV 45) or gastric adenocarcinoma or gastricMALT lymphoma associated with Helicobacter pylori infection. In otherembodiments, the formula 1 compound(s) is administered to a subject whohas a hyperproliferation condition that appears to not be associatedwith a pathogen, e.g., melanoma, or a cancer or precancer arising in thethroat, esophagus, stomach, intestine, colon, ovary, lung, breast orcentral nervous system.

[0548] In an exemplary embodiment, human patients suffering frommelanoma or melanoma precursor lesions are treated with a topical creamformulation containing 2-20% BrEA (w/w). The cream is applied to primarynevi (dysplastic nevi or common acquired nevi), primary cutaneousmelanomas, secondary cutaneous melanomas and the skin surrounding thenevi or melanomas. The areas to be treated are washed with soap orswabbed with an alcohol (e.g., ethanol or isopropanol) prior toadministering the cream, when this is practical. About 0.1-0.4 g ofcream, depending on the size of the treated area, is applied once ortwice per day per treated region or lesion for about 10-20 days. Thecream is left undisturbed at the administration site for about 15-30minutes before the patient resumes normal activity. Progression of thenevi and melanomas is retarded in the majority of patients andsignificant regression is observed for some lesions. Following initialtreatment, the formulation is administered every other day for at least1 to 4 months using the same dosing described for the initial round oftreatment. For these patients, standard therapy to treat precursorlesion or melanoma, e.g., dimethyl triazeno imidazole carboxamide ornitrosoureas (e.g., BCNU, CCNU), is optionally started or continuedaccording to the recommendations of the patient's doctor and with thepatient's informed approval. In cases where a tumor or precursor lesionis surgically removed and the site has sufficiently healed, the patientoptionally continues using the topical formulation at the site and theadjacent surrounding area every other day for at least 1 to 4 months. Insome of these embodiments, a formula 1 compound(s) is administered dailycontinuously as an oral composition or formulation, e.g., for a formula1 compound(s) that is a new compound per se. BrEA is optionally alsoadministered systemically using, e.g., a formulation described in theexamples below to deliver 1-5 mg/kg/day every other day for about 1 weekto about to 4 months, e.g., in the case of malignant melanoma.

[0549] Insufficient Th1 immune responses are ofter associated with viralinfection. Viral infections may arise from DNA or RNA viruses, e.g.,herpesviruses, hepadnaviruses, adenoviruses, retroviruses, togaviruses,alphaviruses, arboviruses, flaviviruses, rhinoviruses, papillomavirusesand/or pestiviruses. Exemplary viruses have been described. See, forexample B. N. Fields, et al., editors, Fundamental Virology, 3^(rd)edition, 1996, Lippencott-Raven Publishers, see chapter 2 at pages23-57, including table 4 at pages 26-27, table 5 at pages 28-29, chapter17 at pages 523-539, chapters 26-27 at pages 763-916, chapter 32 atpages 1043-1108 and chapter 35 at pages 1199-1233. As used herein,retroviruses include human and animal viruses, e.g., HIV-1, HIV-2, LAV,human T-cell leukemia virus I (“HTLV I”), HTLV II, HTLV II, SIV, SHIV,FIV, FeLV. Additional viruses, including their genogroups, clades,isolates, strains and so forth, that may establish a virus infectioninclude human hepatitis C virus (“HCV”), human hepatitis B virus(“HBV”), human hepatitis A virus (“HAV”), duck hepatitis virus,woodchuck hepatitis virus, human (“HPV”, e.g., HPV 6, HPV 11, HPV 16,HPV 18, HPV 31, HPV 45) or animal papilloma viruses, Poliovirus, Herpessimplex virus 1 (“HSV-1”), Herpes simplex virus 2 (“HSV-2”), humanHerpesvirus 6 (“HHV-6”), human Herpesvirus 8 (“HHV-8”), Dengue virus(types 1-4), Western Equine Encephalitis Virus, Japanese EncephalitisVirus, Yellow Fever Virus and Bovine Viral Diarrhea Virus.

[0550] Other conditions where an immune imbalance or an excessive Th2immune response is involved include autoimmune diseases such as SLE(systemic lupus erythematosus), osteoporosis, multiple sclerosis,myasthenia gravis, Graves disease, mite-associated ulcerativedermatitis, rheumatoid arthritis and osteoarthritis. Excessive Th2immune responses are also associated with an unwanted symptom orpathology, e.g., fatigue, pain, fever or an increased incidence ofinfection, that is associated with aging, allergy and inflammationconditions such as allergic bronchopulmonary aspergillosis in cysticfibrosis patients, atopic asthma, allergic respiratory disease, allergicrhinitis, atopic dermatitis, subepithelial fibrosis in airwayhyperresponsiveness, chronic sinusitis, perennial allergic rhinitis,Crohn's disease (regional enteritis), ulcerative colitis, inflammatorybowel disease, fibrosing alveolitis (lung fibrosis).

[0551] Other clinical indications that have an association with or havea symptom(s) that is consistent with an excessive Th2 immune response,e.g., fatigue, pain, fever or an increased incidence of infection, areschizophrenia, acute myelitis, sarcoidosis, burns, trauma (e.g., bonefracture, hemorrhage, surgery) and immune responses toxenotransplantation. This common underlying immune component in at leastpart of the pathology of all of these conditions allows a single agentto be effectively used to treat the condition or to treat one or moresymptoms that are associated with insufficient Th1 responses or withexcessive Th2 responses. In all of the conditions where an insufficientTh1 response or an unwanted Th2 response is present, amelioration of oneor more symptoms associated with the condition is accomplished byadministering an effective amount of a formula 1 compound according tothe methods described herein. Thus, one may intermittently administer aformula 1 compound using a formulation and a route of administration asdescribed herein.

[0552] In some applications, the formula 1 compound(s) may directlyand/or indirectly interfere with replication, development orcell-to-cell transmission of a pathogen such as a virus or a parasite(malaria). Improvement in a subject's clinical condition may arise froma direct effect on an infectious agent or on a malignant cell.Interference with cellular replication can arise from inhibition of oneor more enzymes that a parasite or an infected cell uses for normalreplication or metabolism, e.g., glucose-6-phosphate dehydrogenase,which affects cellular generation of NADPH (see, e.g., Raineri et al.,Biochemistry 1970 9: 2233-2243). This effect may contribute tocytostatic effects that some formula 1 compounds can have. Modulation ofcellular enzymes expression or activity may also interfere withreplication or development of a pathogen, e.g., HIV or malaria parasitesor with replication or development of neoplastic cells, e.g., inhibitionof angiogenesis. Clinical improvement will also generally result from anenhanced Th1 immune response.

[0553] In other applications, embodiments are a method comprisingcontacting a formula 1 compound(s) with a cell(s), whereby the formula 1compound(s) forms a complex with a steroid hormone receptor or resultsin the modulation of a biological activity. The steroid hormone receptormay be an orphan nuclear hormone receptor that displays a moderate orhigh binding affinity for the formula 1 compound(s). In someembodiments, the steroid receptor is a known steroid receptor.Biological effects from interaction of a formula 1 compound and areceptor can lead to interference with the replication or development ofa pathogen or the cell(s) itself. For example, expression of HIVtranscripts in HIV-infected cells may be altered. The receptor-formula 1compound complex may directly interfere with LTR-dependent transcriptionof HIV genes, leading to reduced viral replication.

[0554] Invention embodiments include compositions comprising a partiallypurified or a purified complex comprising a formula 1 compound and asteroid receptor. Such a steroid receptor(s) may be an orphan steroidreceptor or a characterized steroid receptor, where either type bindsthe formula 1 compound with a moderate or high binding affinity, e.g.,less than about 0.5−10×10⁻⁶ M, usually less than about 1×10⁻⁷ M, or, forhigher affinity interactions, less than about 0.01−10×10⁻⁹ M. Theformula 1 compound(s) may also enhance immune responses such that bothimmune responses and altered intracellular conditions simultaneouslyexist to ameliorate one or more of the pathological conditions describedherein.

[0555] The formula 1 compounds may be used to identify receptors thatmodulate biological responses, e.g., receptors that participate ineffecting enhanced Th1 cytokine synthesis. Invention embodiments includea method, “Method 1”, which permits the determination of one or moreeffects of a test compound on a steroid receptor in various biologicalsystems. Generally, the test compound is a formula 1 compound. Suchsystems include cells containing a DNA construct that constitutively orinducibly expresses a steroid receptor(s) of interest, e.g., SXR, CARβ,RXR, PXR, PPARα or mixtures or dimers thereof, e.g., SXR/RXR. In otherbiological systems, the steroid receptor can be under thetranscriptional control of a regulatable promoter. Alternatively, theexpression another gene such as a steroid-inducible gene, e.g., asteroid-inducible cytochrome P-450. For this method, a source of steroidreceptors is generally combined with a means of monitoring them, e.g.,by measuring the transcription of a gene regulated by the receptor.Cells that comprise the steroid receptor and optional monitoring meansare sometimes referred to herein as the “biological system.” Sources ofsteroid receptors include cell lines and cell populations that normallyexpress the steroid receptor of interest and extracts obtained from suchcells. Another source for a useful biological system for purposes ofthis method is tissues from experimental animals that express thereceptor.

[0556] In one aspect, method 1 allows one to determine one or moreeffects of a formula 1 compound on a steroid receptor using a methodthat comprises (a) providing a biological system, e.g., a cell extract,cells or tissue, comprising cells having a plurality of steroidreceptors that comprise monomers, homodimers or heterodimers thatcomprise a steroid receptor, e.g., SXR, CAR-β, RXR, PPARα, PXR or dimersthat comprise one or more of these; (b) activating or inhibiting theplurality of monomers, homodimers or heterodimers that comprise thesteroid receptor by contacting the cells with a steroid receptor (e.g.,SXR, CAR-β, RXR, PPARα or PXR) agonist or antagonist; (c) removingsubstantially all of the steroid receptor agonist or antagonist from thecells; (d) determining an activity of the plurality of monomers,homodimers or heterodimers that comprise the steroid receptor while inan activated state in the absence of agonist or antagonist; (e) exposingthe cells to the test compound; (f) determining at least one effect ofthe test compound on the activity of the plurality of monomers,homodimers or heterodimers that comprise one or more of the steroidreceptors while they remain substantially free of agonist or antagonist;and (g) optionally classifying the test compound as an agonist or anantagonist of the steroid receptor, or a neutral compound having littleor no detectable effect.

[0557] The effects that method 1 can measure include determining ormeasuring an effect on a gene whose expression is affected by thesteroid receptor. The gene could be a gene associated with apathological condition such as an infectious agent, an immune disorderor a hyperproliferation condition.

[0558] Thus, another aspect of method 1, “method 1A”, is determining ifa chemical not previously known to be a modulator of proteinbiosynthesis can transcriptionally modulating the expression of a genethat encodes a protein associated with the maintenance or treatment ofone or more symptoms of a pathological condition. This method comprises:(a) contacting a sample which comprises eucaryotic cells with a formula1 compound, wherein the eucaryotic cells comprise a plurality of steroidreceptor proteins and a DNA construct containing in 5′ to 3′ order (i) amodulatable transcriptional regulatory sequence of the gene encoding theprotein of interest, (ii) a promoter of the gene encoding the protein ofinterest, and (iii) a reporter gene which expresses a polypeptidecapable of producing a detectable signal, coupled to, and under thecontrol of, the promoter, under conditions such that the chemical, ifcapable of acting as a transcriptional modulator of the gene encodingthe protein of interest, causes a measurable or detectable signal to beproduced by the polypeptide expressed by the reporter gene; (b)quantitatively determining the amount of the signal so produced; and (c)optionally comparing the amount so determined with the amount ofproduced signal detected in the absence of any chemical being tested orupon contacting the sample with other chemicals so as to identify thechemical as one that causes a change in the detectable signal producedby the polypeptide, and determining whether the chemical specificallytranscriptionally modulates expression of the gene associated with themaintenance or treatment of one or more symptoms of the pathologicalcondition.

[0559] In conducting method 1A, one typically contacts a sample thatcontains a predefined number of identical or essentially identicaleucaryotic cells with a predetermined concentration of a compound offormula 1. The eucaryotic cells comprise a DNA construct that is madeusing conventional molecular biology methods and protocols. Generallythe DNA construct contains in 5′ to 3′ order (i) a transcriptionalregulatory sequence that participates in modulating expression of thegene that is associated with maintaining or treating the pathologicalcondition, (ii) the gene's promoter, and (iii) a reporter gene whichexpresses a polypeptide capable of producing a detectable signal,coupled to, and under the control of, the promoter. The construct ismaintained under conditions such that the formula 1 compound, if capableof acting as a transcriptional modulator of the gene encoding theprotein of interest, causes a measurable or detectable signal to beproduced by the polypeptide expressed by the reporter gene. Oncesufficient time for generation of a detectable response or signal haspassed, one can determine the amount of the signal produced. Typicallythe response or signal is measured quantitatively, but a qualitativemeasurement can be useful for rapid screening purposes.

[0560] For method 1A, one can also optionally compare the detectablesignal with the amount of produced signal that (i) one detects in theabsence of any formula 1 compound or (ii) when contacting the samplewith other chemicals, which identifies the formula 1 compound as achemical that causes a change in the detectable signal the polypeptideproduces. One then typically determines whether the formula 1 compoundspecifically transcriptionally modulates expression of the geneassociated with the maintenance or treatment of one or more symptoms ofthe pathological condition.

[0561] Other aspects of the method 1 and 1 A include a screening methodcomprising separately contacting each of a plurality of identical,essentially identical or different samples, each sample containing apredefined number of such cells with a with a predeterminedconcentration of each different formula 1 compound to be tested, e.g.,wherein the plurality of samples comprises more than about 1×10³ or morethan about 1×10⁴ samples or about 0.5−5×10⁵ samples. In other aspectsone determines the amount of RNA by quantitative polymerase chainreaction. In any of methods 1 or 1A, a formula 1 compound such as anyone of those described or named herein may be utilized.

[0562] Aspects of the invention include another method, “method 2”,which centers on identifying a gene whose expression is modulated by acandidate binding partner for infectious disease therapeutic agents.Typically the binding partner is a steroid receptor, e.g., a monomer,homodimer or heterodimer that comprises SXR, CAR-β, PXR, PPARα or RXR ora homolog or isoform thereof. The steroid receptor is typically presentas a complex that comprises, e.g., the formula 1 compound and theregulated gene's DNARS, which the steroid receptor, or a complex thatcomprises the steroid receptor, recognizes and specifically binds to.Such complexes can also comprise a transcription factor that binds tothe steroid receptor or to nucleic acid sequences adjacent to or nearthe DNARS. Exemplary transcription factors that may be present includeone or more of ARA54, ARA55, ARA70, SRC-1, NF-κB, NFAT, AP1, Ets, p300,CBP, p300/CBP, p300/CPB-associated factor, SWI/SNF and human homologs ofSWI/SNF, CBP, SF-1, RIP140, GRIP1 and Vpr. In general, one provides afirst and a second group of cells in vitro or in vivo and contacts thefirst group of cells with the infectious disease therapeutic agent, butdoes not contact the second group of cells in vitro or in vivo with theinfectious disease therapeutic agent. Recovering RNA from the cells, orgenerating cDNA derived from the RNA, is accomplished by conventionalprotocols. Analysis of the RNA, or cDNA derived from the RNA, from thefirst and the second group of cells identifies differences between them,which one can use to identify a gene whose regulation is modulated bythe candidate-binding partner for the infectious disease therapeuticagent or any DNARS associated with that gene.

[0563] An aspect of method 2 is determining the capacity of a formula 1compound to modulate, or participate in the modulation of, thetranscription of a gene associated with the maintenance or treatment ofone or more symptoms of a pathological condition. It is expected that ingeneral, the formula 1 compounds will cause an increase in thetranscription of such genes. The pathological condition is typically oneassociated with an infectious agent, e.g., virus, parasite or bacterium,but can also include an immune condition, e.g., an autoimmune conditionor an immune deficiency. The pathological condition may also be aninsufficient immune response to an infection or an insufficient responseto a hyperproliferation condition or malignancy. Other pathologicalconditions that one can apply the method to are inflammation conditions.

[0564] In some aspects, the formula 1 compounds used in method 2 will belabeled. Such compounds are prepared by conventional methods usingstandard labels, such as radiolabels, fluorescent labels or other labelsas described herein and in the cited references.

[0565] An embodiment of method 2 involves analyzing the RNA, or cDNAderived from it, by subtraction hybridization. In this embodiment, theRNA or cDNA obtained from the first and second groups of cells ishybridized and the resulting duplexes are removed. This allows recoveryof nucleic acids that encode genes whose transcription is modulated bythe candidate-binding partner, which is usually a steroid receptor. Onecan use conventional methods to amplify and obtain nucleic acid andprotein sequence information from the nucleic acids recovered by thismethod. The nucleic acid sequences that are transcriptionally induced orrepressed by the formula 1 compound are candidate-binding partners.

[0566] A transcriptionally induced gene(s) will be enriched in the group1 cells treated with the formula 1 compound, while any repressed gene(s)will be depleted or absent. In these embodiments, the RNA recoveredafter removal of duplexes is typically amplified by standard RT-PCR orPCR protocols. These protocols typically use specific sets of randomprimer pairs, followed by analysis of the amplified nucleic acids by gelelectrophoresis. Nucleic acids that are induced by the formula 1compound will appear as a band(s), usually duplex DNA, that is notpresent in the control or second set of cells. Nucleic acids that aretranscriptionally repressed by the formula 1 compound's binding partnerwill be depleted or absent in the first group of cells. Once such genecandidates are identified, they can be cloned and expressed and thecapacity of the DNARS associated with the gene to form a complex thatcomprises a candidate binding partner and an optionally labeled formula1 compound is analyzed by conventional methods, e.g., equilibriumdialysis, affinity chromatography using, e.g., the DNARS immobilized ona column, or coprecipitation of complexes that comprise an optionallylabeled DNARS and candidate binding partner using anti-binding partnerantibodies. Nucleic acid sequence analysis is usually used to identifyregions adjacent to the coding regions of the regulated gene to identifyany DNARS associated with the gene. The identity of a DNARS can beestablished by the binding to the DNARS of complexes that comprise acandidate binding partner, e.g., a steroid receptor, and optionally alsocomprise a formula 1 compound. The location and identity of the DNARScan be accomplished by DNA footprinting or other methods for detectingbinding interactions. The DNARS, the receptor or the formula 1 compoundcan be labeled in these variations of method 2.

[0567] In general, the second group of cells will be identical oressentially identical to the first group of cells. In embodiments (forboth methods 1 and 2) where the cells are “essentially identical”, thefirst or the second group of cells may differ from each other by thepresence or absence of a DNA construct(s) that expresses (i) a steroidreceptor and/or (ii) an easily detected protein, e.g., aβ-galactosidase, a peroxidase, a phosphatase, or a chloramphenicolacetyltransferase, whose transcriptional regulation is usually modulatedby a steroid receptor. In these embodiments, the difference between thefirst and the second group of cells is used to facilitate the analysisof the biological effects of the formula 1 compound and the steroidreceptor-binding partner. Groups of cells are considered “identical” ifthey do not display known or obvious morphological or geneticdifferences.

[0568] Usually, the second group of cells will serve as a control, andthey will thus not be exposed to any formula 1 compound before obtainingthe RNA or cDNA. But, for some embodiments, one can expose the secondgroup of cells to a known agonist or antagonist of the steroidreceptor-binding partner. This allows one to compare the potency of theformula 1 compound with the potency of the agonist or antagonist.

[0569] In other embodiments, one can modify method 2 by providing athird group of cells, which is optionally used as an untreated controlwhen the second group of cells is treated with a steroid receptoragonist or antagonist. In these embodiments, one will typically comparethe effect of the formula 1 compound and the agonist or the antagonistof the expression of a gene or DNA construct. The DNA construct wouldcomprise a promoter or other regulatory sequences that are subject totranscriptional modulation, usually increase transcription, by theformula 1 compound in concert with its binding partner.

[0570] Exemplary mammalian and other steroid receptors, including orphansteroid receptors, their homologs, isoforms and co-factors (e.g.,co-repressors, transcription factors, gene promoter regions orsequences) that these complexes can comprise are steroidogenic factor-1(SF-1), chicken ovalbumin upstream promoter-transcription factor(COUP-TFI) and its mammalian homologs, silencing mediator for retinoidand thyroid hormone receptor (SMRT) and its mammalian homologs, NF-E3,COUP-TFII and its mammalian homologs, testicular orphan receptor TR2,thyroid hormone α1 (TR α1), retinoid X receptor α, TR α1/RXR αheterodimer, direct repeat-4 thyroid hormone response element (DR4-TRE),estrogen receptor (ER), estrogen receptor related α (ERRα), estrogenreceptor related β (ERRβ), steroid xenobiotic receptor (SXR), hepatocytenuclear factor 4 (HNF-4), hepatocyte nuclear factor 3 (HNF-3), liver Xreceptors (LXRs), LXRα, estrogen receptor α (ERα), constitutiveandrostane receptor-β (CAR-β), RXR/CAR-β heterodimer, short heterodimerpartner (SHP), SHP/ERα heterodimer, estrogen receptor β, SHP/ERPheterodimer, testicular orphan receptor TR4, TR2/TR4 heterodimer,pregnane X receptor (PXR) and isoforms, cytochrome P-450 monooxygenase3A4 gene promoter region and isoforms, HNF-4/cytochrome P-450monooxygenase 3A4 gene promoter region and isoforms complex, HIV-1 longterminal repeat (LTR), HIV-2 LTR, TR2/HIV-1 LTR complex, TR4/HIV-1 LTRcomplex, TR4/HIV-1 LTR complex, TR α1/TR4/HIV-1 LTR complex, TR2isoforms (TR2-5, TR7, TR9, TR11), DAX-1, DAX-1/steroidogenic acuteregulatory protein gene promoter region, RevErb, Rev-erbA α, Rev-erb β,steroid receptor coactivator amplified in breast cancer (AIB 1),p300/CREB binding protein-interacting protein (p/CIP), thyroid hormonereceptor (TR, T3R), thyroid hormone response elements (T3REs),constitutive androstane receptor (CAR), Xenopus xSRC-3 and mammalian(human) homologs, TAK1, TAK1/peroxisome proliferator-activated receptorα (PPARα) complex, PPARα/RXRα complex, TAK-1/RIP-140 complex, retinoicacid receptor (RAR), RARβ, TR4/RXRE complex, SF-1/steroid hydroxylasegene promoter region, SF-1/oxytocin gene promoter region, SF-1/ACTHreceptor gene promoter region, rat Ear-2 and mammalian homologs, humanTR3 orphan receptor (TR3), RLD-1, OR-1, androgen receptor,glucocorticoid receptor, estrogen receptor, progesterone receptor,mineralcorticoid receptor, OR1, OR1/RXRα complex, TIF-1, CBP/P300complex, TRIP1/SUG-1 complex, RIP-140, SRC1α/P160 complex andTIF-2/GRIP-1 complex, RAR/N-CoR/RIP13 complex, RAR/SMRT/TRAC-2 complex,and the DNARS 5′ AGGTCANAGGTCA 3′ or 5′ TGCACGTCA 3′. One of thesecomplexes can be included in invention methods when, e.g., they areperformed in cell-free assays. Formation of these complexes in cells isfacilitated by inserting into the cells a DNA construct(s) thatexpresses one or more of these proteins, e.g., mammalian or yeast cellscontaining a stable DNA construct or a construct used for transienttransfection assays. Methods to perform assays or to induce biologicalresponses in vitro or in vivo using the formula 1 compounds as agonists,antagonists or as reference standards are essentially as described, see,e.g., U.S. Pat. Nos. 5,080,139, 5,696,133, 5,932,431, 5,932,555,5,935,968, 5,945,279, 5,945,404, 5,945,410, 5,945,412, 5,945,448,5,952,319, 5,952,371, 5,955,632, 5,958,710, 5,958,892, 5,962,443;International Publication Numbers WO 96/19458, WO 99/41257, WO 99/45930.The complexes or assay systems, that comprise a formula 1 compound andthat are employed in the practice of these methods are included asaspects of the invention.

[0571] The formula 1 compounds typically interact with one or morebiological ligands to efect a biological response. To facilitate theidentification of candidate binding partners for the formula 1compounds, one can use a radiolabeled formula 1 compound that is linkedto a support, usually a solid support, as a means to recover thecandidate binding partners. The formula 1 compound can be linked to thesupport through, e.g., the 3-, 7-, 16- or 17-position of the steroidnucleus. Linking agents are known for such uses and includehomobifunctional and heterobifunctional agents, many of which arecommercially available. The linker one uses will typically compriseabout 2-20 linked atoms. The linked atoms usually comprise mostlycarbon, with one, two or three oxygen, sulfur or nitrogen atoms thatreplace one or more carbon atoms. One can use a cDNA expression librarythat one has made from suitable cells or tissues as a source ofcandidate binding partners. The cells or tissues can be obtained from amammalian or a vertebrate host, e.g., human, mouse, bird, primate, orfrom other sources, e.g., insects (e.g., Drosophila), otherinvertebrates (e.g., yeast, bacteria, Mycoplasma sp., Plasmodium sp.,Tetrahymena sp., C. elegans) or other organism groups or species listedherein or in the cited references. Suitable tissues include skin, livertissue or cells, including hepatocytes and Kupfer cells, fibrocytes,monocytes, dendritic cells, kidney cells and tissues, brain or othercentral nervous system cells or tissues, including neurons, astrocytesand glial cells, peripheral nervous system tissues, lung, intestine,placenta, breast, ovary, testes, muscle, including heart or myocytetissue or cells, white blood cells, including T cells, B cells, bonemarrow cells and tissues, lymph tissues or fluids and chondrocytes.

[0572] Typically a candidate-binding partner that one isolates from anon-human source will have a human homolog that has similar bindingproperties for the formula 1 compound. Non-human candidate-bindingpartners can thus be used to facilitate recovery of the human homologs,e.g., by preparing antiserum for precipitating the human homolog from asolution that comprises the human homolog or by comparing the sequenceof the non-human candidate-binding partner with known human genesequences. Once a source of the candidate-binding partner is obtained,it can be contacted with labeled formula 1 compound, usuallyradiolabeled with, e.g., ¹⁴C or ³H, and complexes that comprise thelabeled formula 1 compound and the candidate-binding partner isrecovered using, e.g., affinity chromatography or antibody precipitationmethods. The recovery of the complex provides a source of at leastpartially purified candidate-binding partner, i.e., thecandidate-binding partner is enriched, e.g., at least 10-fold enriched,or at least 100-fold enriched, or at least 500-fold enriched, comparedto its abundance in the original candidate-binding partner sourcematerial.

[0573] Aspects of the invention include a composition comprising apartially purified (purified at least about 2-fold to about 10-foldrelative to natural sources, e.g., cells or a cell lysate) comples or apurified (purified at least about 20-fold to about 5000-fold relative tonatural sources, e.g., cells or a cell lysate) complex (where thepartially purified or purified complex is optionally isolated)comprising a formula 1 compound and a steroid receptor, a serumsteroid-binding protein (e.g., human serum albumin, α1-acidglycoprotein, sex hormone-binding globulin, testosterone-bindingglobulin, corticosteroid-binding globulin, androgen binding protein(rat)) or another binding partner, e.g., transcription factor or DNARS.An aspect of these compositions includes a product produced by theprocess of contacting the partially purified or the purified compositionwith one or more cells, one or more tissues, plasma or blood.

[0574] Other aspects include a method to determine a biological activityof a formula 1 compound comprising: (a) contacting the formula 1compound(s) with a cell or cell population; (b) measuring one or more of(i) a complex between a binding partner and the formula 1 compound, (ii)proliferation of the cell or cell population, (iii) differentiation ofthe cell or cell population (iv) an activity of a protein kinase C, (v)a level of phosphorylation of a protein kinase C substrate, (vi)transcription of one or more target genes, (vii) inhibition of thecellular response to steroids, e.g., glucocorticoids, (viii) inhibitionof steroid-induced transcription, e.g., glucocorticoids, sex steroids or(ix) inhibition of HIV LTR-driven transcription; and (c) optionallycomparing the result obtained in step (b) with an appropriate control.Aspects of this embodiment include (i) the method wherein the bindingpartner is a steroid receptor, a transcription factor or a DNARS, (ii)the method wherein the biological activity determined is a modulatingactivity of the formula 1 compound for replication or cytopathic effectsassociated with a retrovirus, a hepatitis virus or a protozoan parasite,(iii) the method wherein the biological activity determined is amodulating activity of the formula 1 compound for replication,cytopathic effects associated with the retrovirus, the hepatitis virusor the protozoan parasite or the biological activity determined ismetabolism (assay by ³H-thymidine uptake or other assay as referenced ordescribed herein) of a cell or cell population comprising NK cells,phagocytes, monocytes, macrophages, basophils, eosinophils, dendriticcells, synoviocytes, microglial cells, fibrocytes, transformed(neoplastic) cells, virus-infected cells, bacteria-infected cells orparasite-infected cells, and (iv) the method wherein the target gene isa virus gene, a bacterial gene, a parasite gene, a gene associated withcancer, e.g., wherein the virus gene is a DNA or an RNA polymerase gene,a reverse transcriptase gene, an envelope gene, a protease gene or agene associated with viral nucleic acid replication or a viralstructural gene.

[0575] An embodiment is a method comprising contacting a complex thatcomprises a steroid receptor and a formula 1 compound with atransactivator protein, whereby a complex comprising the steroidreceptor protein, the formula 1 compound and the transactivator proteinforms, wherein the transactivator protein is in (1) a cell or tissueextract (e.g., nuclei, lysate containing nuclei or lysate without nucleifrom a cell(s) or tissue(s)), (2) a partially purified or purified cellor tissue extract, (3) a cell(s) in tissue culture or (4) a cell(s) in asubject, where any of (1)-(4) optionally comprises a target gene (nativegene or introduced by standard gene manipulation techniques) whose levelof expression is optionally assayed after the complex forms. In some ofthese embodiments, the transactivator protein is partially purified orpurified and is in the cell or tissue extract or the partially purifiedor purified cell or tissue extract. The transactivator protein may beTIF-1, CBP/P300, TRIP1/SUG-1, RIP-140, SRC1α/P16O, or TIF-2/GRIP-1. Inany of these embodiments the complex comprising the steroid receptorprotein, the formula 1 compound and the transactivator protein mayincrease or decrease transcription of the target gene compared to asuitable control (e.g., control under same conditions, but lacking anyadded compound that corresponds to the formula 1 compound, or whereanother compound (e.g., a steroid that is known to bind to the steroidreceptor) is used as a benchmark or reference standard against whichaltered target gene expression is measured). In these methods, thetarget gene may be a pathogen gene (e.g., virus, bacterium, parasite,fungus, yeast) or a gene associated with a pathological condition(autoimmunity, inflammation, hyperproliferation).

[0576] The formula 1 compounds are suitable for use in certain describedmethods that use steroids to modulate biological activities in cells ortissues. For example, a formula 1 compound(s) can be used to selectivelyinteract with specific steroid receptors or steroid orphan receptor, ortheir subtypes, that are associated with a pathological condition(s) ina subject, essentially as described in U.S. Pat. No. 5,668,175. In theseapplications, the formula 1 compound may act as a ligand for thereceptor to modulate abnormal expression of a gene product(s) thatcorrelates with the pathological condition (a steroid hormone responsivedisease state). Such genes are normally regulated by steroid hormones.In other applications, one can use the formula 1 compounds to screen forligands that bind to a steroid receptor or steroid orphan receptor andone or more transcription factors (or cofactors) such as AP-1 and/orwith a DNA sequence(s), essentially as described in U.S. Pat. No.5,643,720. Similarly, the formula 1 compounds can be used essentially asdescribed in U.S. Pat. Nos. 5,597,693, 5,639,598, 5,780,220, 5,863,733and 5,869,337. In some of these embodiments, the formula 1 compound(s)is labeled to facilitate its use. Suitable labels are known in the artand include radiolabels (e.g., ³H, ¹⁴C, ³²P, ³⁵S, ¹³¹I, ⁹⁹Tc and otherhalogen isotopes), fluorescent moieties (e.g., fluorescein, resorufin,Texas Red, rhodamine, BODIPY, arylsulfonate cyanines), chemiluminescentmoieties (e.g., acridinium esters), metal chelators, biotin, avadin,peptide tags (e.g., histidine hexamer, a peptide recognized bymonoclonal or polyclonal antibodies), covalent crosslinking moieties.One prepares the labeled compounds according to known methods.

[0577] Methods suitable to measure the biological effects of variouscompounds, e.g., activation, on immune system cells (e.g., NK cells,phagocytes, monocytes, macrophage, neutrophils, eosinophils, dendriticcells, synoviocytes, microglial cells, fibrocytes) have been described,e.g., Jakob et al., J. Immunol. 1998 161:3042-3049, Pierson et al.,Blood 1996 87:180-189, Cash et al., Clin. Exp. Immunol. 1994 98:313-318,Monick et al., J. Immunol. 1999 162:3005-3012, Rosen et al., Infect.Immun. 1999 67:1180-1186, Grunfeld et al., J. Lipid Res. 199940:245-252, Singh et al., Immunol. Cell Biol. 1998 76:513-519, Chesneyet al., Proc. Natl. Acad. Sci. USA 1997 94:6307-6312, Verhasselt et al.,J. Immunol. 1999 162:2569-2574, Avice et al., J. Immunol. 1999162:2748-2753, Cella et al., J. Exp. Med. 1999 189:821-829, Rutalt etal., Free Radical Biol. Med. 1999 26:232-238, Akbari et al., J. Exp.Med. 1999 189:169-178, Hryhorenko et al., Immunopharmacology 199840:231-240, Fernvik et al., Inflamm. Res. 1999 48:28-35, Cooper et al.,J. Infect. Dis. 1999 179:738-742, Betsuyaku et al., J. Clin. Invest.1999 103:825-832, Brown et al., Toxicol. Sci. 1998 46:308-316, Sibeliuset al., Infect. Immunol. 1999 67:1125-1130. The use of formula 1compounds in such methods are aspects of the invention and they permit,e.g., measurement of the biological effects of formula 1 compounds ongenes whose expression is regulated by the formula 1 compound and thesteroid receptor.

[0578] Embodiments include any of the methods described above, e.g.,method 1, wherein the cells or biological system comprises NK cells,phagocytes, monocytes, macrophage, neutrophils, eosinophils, dendriticcells, synoviocytes, microglial cells, glial cells, fibrocytes orhepatocytes, that optionally comprise a DNA construct that expresses oneor two cloned steroid receptors. The method optionally analyzes theeffect of a formula 1 compound on the cells compared to controls.Controls include the use of a known agonist or antagonist for thesteroid receptor or the comparison of cells exposed to a formula 1compound with control cells (usually the same cell type as the treatedcells) that are not exposed to the formula 1 compound. A response, e.g.,activation of the steroid receptor can be measured by known assayscompared to controls.

[0579] The formula 1 compound will, in some cases modulate (increase ordecrease) transcription of one or more genes in the cells. In othercases, the formula 1 compound will enhance lysosome movement in one ormore of the subject's NK cells, phagocytes, monocytes, macrophages,neutrophils, eosinophils, dendritic cells synoviocytes, microglial cellsor fibrocytes. Such effects will typically be mediated directly orindirectly through steroid receptors that act to modulate genetranscription, e.g., cause enhances protein kinase C (PKC) activity inthe cells used in the assay, e.g., PKCα, PKCβ, PKCγ or PKCζ.

[0580] Other related embodiments are a composition comprising apartially purified or a purified complex comprising a formula 1 compoundand a steroid receptor, a serum steroid-binding protein (e.g., humanserum albumin, α1-acid glycoprotein, sex hormone-binding globulin,testosterone-binding globulin, corticosteroid-binding globulin, androgenbinding protein (rat)) or another binding partner, e.g., transcriptionfactor or DNARS. An aspect of these compositions includes a productproduced by the process of contacting the partially purified or thepurified composition with one or more cells, one or more tissues, plasmaor blood.

[0581] Another embodiment comprises a method to determine a biologicalactivity of a formula 1 compound comprising: (a) contacting the formula1 compound(s) with a cell or cell population; (b) measuring one or moreof (i) a complex between a binding partner and the formula 1 compound,(ii) proliferation of the cell or cell population, (iii) differentiationof the cell or cell population (iv) an activity of a protein kinase C,(v) a level of phosphorylation of a protein kinase C substrate, (vi)transcription of one or more target genes, (vii) inhibition of thecellular response to steroids, e.g., glucocorticoids, (viii) inhibitionof steroid-induced transcription, e.g., glucocorticoids, sex steroids or(ix) inhibition of HIV LTR-driven transcription; and (c) optionallycomparing the result obtained in step (b) with an appropriate control.Aspects of this embodiment include (i) the method wherein the bindingpartner is a steroid receptor, a transcription factor or a DNARS, (ii)the method wherein the biological activity determined is a modulatingactivity of the formula 1 compound for replication or cytopathic effectsassociated with a retrovirus, a hepatitis virus or a protozoan parasite,(iii) the method wherein the biological activity determined is amodulating activity of the formula 1 compound for replication,cytopathic effects associated with the retrovirus, the hepatitis virusor the protozoan parasite or the biological activity determined ismetabolism (assay by ³H-thymidine uptake or other assay as referenced ordescribed herein) of a cell or cell population comprising NK cells,phagocytes, monocytes, macrophages, basophils, eosinophils, dendriticcells, synoviocytes, microglial cells, fibrocytes, transformed(neoplastic) cells, virus-infected cells, bacteria-infected cells orparasite-infected cells, and (iv) the method wherein the target gene isa virus gene, a bacterial gene, a parasite gene, a gene associated withcancer, e.g., wherein the virus gene is a DNA or an RNA polymerase gene,a reverse transcriptase gene, an envelope gene, a protease gene or agene associated with viral nucleic acid replication or a viralstructural gene.

[0582] Another embodiment is a method comprising contacting a complexthat comprises a steroid receptor and a formula 1 compound with atransactivator protein, whereby a complex comprising the steroidreceptor protein, the formula 1 compound and the transactivator proteinforms, wherein the transactivator protein is in (1) a cell or tissueextract (e.g., nuclei, lysate containing nuclei or lysate without nucleifrom a cell(s) or tissue(s)), (2) a partially purified or purified cellor tissue extract, (3) a cell(s) in tissue culture or (4) a cell(s) in asubject, where any of (1)-(4) optionally comprises a target gene (nativegene or introduced by standard gene manipulation techniques) whose levelof expression is optionally assayed after the complex forms. In some ofthese embodiments, the transactivator protein is partially purified orpurified and is in the cell or tissue extract or the partially purifiedor purified cell or tissue extract. The transactivator protein may beTIF-1, CBP/P300, TRIP1/SUG-1, RIP-140, SRC1α/P160, or TIF-2/GRIP-1. Inany of these embodiments the complex comprising the steroid receptorprotein, the formula 1 compound and the transactivator protein mayincrease or decrease transcription of the target gene compared to asuitable control (e.g., control under same conditions, but lacking anyadded compound that corresponds to the formula 1 compound, or whereanother compound (e.g., a steroid that is known to bind to the steroidreceptor) is used as a benchmark against which altered target geneexpression is measured). In these methods, the target gene may be apathogen gene (e.g., virus, bacterium, parasite, fungus, yeast) or agene associated with a pathological condition (autoimmunity,inflammation, hyperproliferation).

[0583] The biological effects observed while performing the methodsdescribed herein are expected to usually involve the formation ofcomplexes that contain two or more components. These components caninclude one or more transcription factors or co-regulators orco-repressors of transcription and their homologs and isoforms. Thesefactors and complexes containing them include members of the steroidreceptor coactivator-1 family (SRC-1, SRC-1/serum response factor),NF-κB, NFAT, p300, CBP, p300/CBP, p300/CPB-associated factor, SWI/SNFand human and other homologs, BRG-1, OCT-1/OAF, AP1, Ets, androgenreceptor associated protein 54 (ARA54), androgen receptor associatedprotein 55 (ARA55), androgen receptor associated protein 70 (ARA70),RAC3/ACTR, CREB-binding protein (CPB), SRC-1α, receptor interactingprotein-140 (RIP-140), transcription factor activator protein-1,activation function-2, glucocorticoid receptor-interacting protein-1(GRIP-1), receptor interacting protein-160 (RIP-1 60), suppressor ofgal4D lesions (SUG-1), transcription intermediary factor-1 (TIF-1),transcription intermediary factor-2 (TIF-2), SMRT, N-CoR, N-CoA-1,p/CIP, stroidogenic factor-1 (SF-1), p65 (ReIA), and Vpr encoded by thehuman immunodeficiency virus and its isoforms and homologs. One or moreof these factors can be present in complexes that comprise a formula 1compound and a steroid receptor, such as SXR, PPARα, CAR-β, RXR and/orPXR.

[0584] In a related embodiment, a formula 1 compound is used to exert acytostatic effect on mammalian cells in vitro. Typically such cells arelymphoid cells, e.g., T cell populations from, e.g., blood or organsthat are rich in lymphoid cells (e.g., spleen, lymph tissue or nodes),or transformed T cell lines. Such activity provides an estimate of thepotency of formula 1 compounds to mediate immunological effects, such asenhancing Th1 immune responses or suppressing expression of one or moreTh2-associated cytokines. Thus, an invention method comprises (a)contacting a formula 1 compound and lymphoid cells in vitro, (b)determining the degree of cytostasis that the compound exerts toidentify a cytostatic compound and (c) optionally administering thecytostatic compound to an immune suppressed subject to determine theeffect of the compound on one or more of the subject's immune responsesas described herein, e.g., enhanced Th1 cytokine or cell response ordecreased Th2-associated cytokine expression. Typically, such methodsare conducted using a range of formula 1 compound concentrations andsuitable controls, such as a known cytostatic agent or a blank thatcontains solvent that lacks the formula 1 compound. Inhibition of cellproliferation is measured by standard methods. Methods to measure thecytoststic effects of the compounds includes measuring viable cellnumbers in treated and untreated cultures or by measuring DNA synthesisusing e.g., ³H-thymidine incorporation into DNA in treated and untreatedcultures. Typical ranges of formula 1 concentrations in the cell growthmedium are about 0.1 μM to about 100 μM, using about 4-6 differentconcentrations of compounds with a fixed number of cells (e.g., about0.4×10⁵ to about 5×10⁵). The formula 1 compound is left in contact withthe cells in tissue culture for a sufficient time to observe cytostasis,e.g., about 16 hours to about 6 days, typically about 24-72 hours. Inthese embodiments, one may optionally screen for modulation of abiological activity of a steroid receptor, e.g., activation of PPARα,which may be associated with the cytostasis the compound induced.

[0585] In some applications, the formula 1 compound(s) appears to bringabout an improvement of one or more of the symptoms associated with aninfection or a condition. For example, treatment of subjects who areimmune suppressed, e.g., from a retrovirus infection, cancerchemotherapy or other cause, generally show improvement of one or moreassociated symptoms, such as weight loss, fever, anemia, fatigue orreduced infection symptoms that are associated with a secondaryinfection(s), e.g., HSV-1, HSV-2, papilloma, human cytomegalovirus(“CMV”), Pneumocystis (e.g., P. carinii) or Candida (C. albicans, C.krusei, C. tropicalis) infections. The formula 1 compounds are alsouseful to facilitate immune system recovery in autologous bone marrowtransplant or stem cell transplant situations. In some embodiments, theformula 1 compound(s) is administered as a nonaqueous liquid formulationas described herein or the formula 1 compound(s) is administeredaccording to any of the intermittent dosing protocols described hereinusing a solid or liquid formulation(s). In the case of a subject who hasa retroviral infection with symptoms that include one or more of, arelatively low CD4 count (e.g., about 10-200, usually about 20-100), oneor more additional pathogen infections (HSV-1, HSV-2, HHV-6, HHV-8, CMV,HCV, a HPV, P. carinii or Candida infection) and one or more of anemia,fatigue, Kaposi's sarcoma, fever or involuntary weight loss (at leastabout 5% of body weight), administration of about 0.1 to about 10mg/kg/day (usually about 0.4 to about 5 mg/kg/day) of a formula 1compound(s) to the subject typically results in noticeable improvementof one or more of the symptoms within about 1-4 weeks. In otherembodiments, the formula 1 compound(s) is administered to a subject whohas a condition that appears to be associated with a viral infection,e.g., pneumonia or retinitis associated with CMV, nasopharyngealcarcinoma or oral hairy leukoplakia associated with Epstein-Barr virus,progressive pancephalitis or diabetes associated with Rubella virus oraplastic crisis in hemolytic anemia associated with Parvovirus 19.

[0586] In an exemplary embodiment, human patients infected with HCV aredosed with an aqueous isotonic α-cyclodextrin or β-cyclodextrinformulation containing about 20 mg/mL BrEA. The formulation is deliveredintravenously in a single daily dose or two subdoses per day. Thepatients are dosed with 1 to 10 mg/kg/day for 4 to 10 days, followed byno dosing for 5 to 30 days, followed by dosing again with thecyclodextrin formulation for 4 to 10 days. The dosing regimen isrepeated one, two or more times. Clinical markers for HCV infection arefollowed during treatment, e.g., viral nucleic acid in the blood orplasma, liver enzyme levels in the blood or plasma (e.g., AST/SGOT,ALT/SGPT, alkaline phosphatase). For these patients, a standard anti-HCVtreatment(s), e.g., interferon and/or ribavirin, is optionally startedor continued according to the recommendations of the patient's doctorand with the patient's informed approval. In some of these embodiments,a formula 1 compound(s) is administered daily continuously as acomponent in an oral or parenteral composition or formulation, e.g., fora formula 1 compound(s) that is a new compound per se. BrEA isoptionally also administered systemically using, e.g., the formulationof example 1 to deliver 1-5 mg/kg/day every other day for about 1 to 4months, or an oral formulation to deliver about 5-40 mg/kg/day everyother day for about 1 to 4 months.

[0587] In any of the embodiments disclosed herein, one can optionallyadminister an additional therapeutic treatment in conjunction with,i.e., before, during or after, administration of a formula 1 compound(s)to a subject(s). For example, in subjects who have a viral or parasiteinfection and are in the course of administration of a formula 1compound, other treatments can also be administered to the subject,e.g., nucleoside analogs for viral infections or chloroquine formalaria. Such additional treatments will typically include standardtherapies for the subject's pathological condition(s), but they can alsoinclude experimental or other treatments. For example, one cancoadminister vitamins (multivitamins, individual vitamins), antioxidantsor other agents (vitamin E, allopurinol), nutritional supplements(liquid protein or carbohydrate preparations) or other therapies as thepatient's medical condition warrants and the patient's doctorrecommends. Any of these additional treatments can be coupled with theadministration of any of the formula 1 compounds, e.g., BrEA, an ester,carbamate, carbonate or amino acid or peptide conjugate thereof, in anyof the embodiments described herein.

[0588] Such additional treatments are apparent to the skilled artisan.Such treatments are selected based on the condition(s) to be treated,cross-reactivities of ingredients and pharmaco-properties of thecombination. For example, when treating retroviral infections in a humanor other subject, the formula I compounds are combined with one or morereverse transcriptase inhibitors, protease inhibitors, antibiotics oranalgesics. Suitable formula 1 compounds include those described, e.g.,in compound groups 1 through 42-25-20-6 and elsewhere herein. Exemplaryreverse transcriptase inhibitors are AZT, 3TC, D4T, ddl, ddC, adefovirdipivoxil,9-[2-(R)-[[bis[[(isopropoxycarbonyl)oxy]methoxy]-phosphinoyl]methoxy]propyl]adenine,(R)-9-[2-(phosphonomethoxy)propyl]-adenine and adefovir. Exemplaryprotease inhibitors are indinavir, nelfinavir, ritonavir, crixivan andsequanavir. Fusion inhibitors may also be used, e.g., HIV fusioninhibitors. When treating viral infections of the respiratory system orother systems, e.g., hepatitis C virus (“HCV”) or influenza virusinfection (e.g., influenza A or B), the compositions of the inventionare optionally used in conjunction with antivirals (such asγ-interferon, amantidine, rimantadine, ribavirin or compounds disclosedin U.S. Pat. No. 5,763,483 (especially compounds recited in claims 1 and2) and 5,866,601), mucolytics, expectorants, bronchodilators,antibiotics, antipyretics, or analgesics.

[0589] In some embodiments, formula 1 compound(s) are administered tosubjects who have a parasite or bacterial infection, to slow theprogression of infection, interfere with replication or development ofthe infectious agent or to ameliorate one or more of the associatedsymptoms, e.g., weight loss, anemia or secondary infections. Parasitesare malaria parasites, sleeping sickness parasites and parasitesassociated with gastrointestinal infections. Parasites and bacteriainclude species, groups, genotypes, strains or isolates ofgastroentestinal helminths, microsporidia, isospora, cryptosporidia(Cryptosporidium parvum), Mycobacterium (M. avium, M. bovis, M. leprae,M. tuberculosis, M. pneumoniae. M. penetrans), Mycoplasma (M.fermentans, M. penetrans, M. pneumoniae), Trypanosoma (T. brucei, Tgambiense, T. cruzi, T. evansi), Leishmania (L. donovani, L. major, L.braziliensis), Plasmodium (P. falciparum, P. knowlesi, P. vivax, P.berghei), Ehrlichia (E. canis, E. chaffeensis, E. phagocytophila, E.equi, E. sennetsu), Babesia microti, Haemophilus (H. somnus, H.influenzae), Brucella (B. militensis, B. abortus), Bartonella (B.henselae), Bordetella (B. bronchiseptica, B. pertussis), Escherichia (E.coli), Salmonella (S. typhimurium), Shigella (S. flexneri), Pseudomonas(P. aeruginosa), Neisseria (N. gonorrhoeae, N. meningitidis),Streptococcus, Staphylococcus (S. aureus), Rickettsia (R. rickettsii),Yersinia (Y. enterocolitica), Legionella pneumonia and Listeria (L.monocytogenes).

[0590] One or more of the invention intermittent dosing protocols or oneor more of the liquid non-aqueous formulations described herein can beapplied by routine experimentation to any of the uses or applicationsdescribed herein. For a formula 1 compound(s) that is a new compound perse, the compound(s) can be administered to a subject according to aninvention intermittent dosing protocol(s) or by other protocols, e.g.,continuous daily dosing of a single dose or two or more subdoses perday. In addition any of the formula 1 compounds, e.g., one or moreformula 1 compounds that are new per se, can be present in any solid orliquid formulation described herein. These formulations and dosingprotocols can be applied by routine experimentation to any of the usesor applications described herein.

[0591] Numbered Embodiments.

[0592] Several aspects of the invention and related subject matterincludes the following numbered embodiments.

[0593] In some aspects, the invention relates to non-aqueous liquidformulations that comprise a formula 1 compound. Exemplary embodimentsare as follows.

[0594] 1. A composition comprising one or more compounds of formula 1 orformula 2 and one or more nonaqueous liquid excipients, wherein thecomposition comprises less than about 3% v/v water.

[0595] 2. The composition of embodiment 1 wherein the one or moreformula 1 compounds has the structure

[0596] wherein R⁷ and R⁹ independently are —CHR¹⁰—, —CH₂—, —CH═, —O—,—S— or —NH—, wherein R¹⁰ is —OH, —SH, C₁₋₁₀ optionally substitutedalkyl, C₁₋₁₀ optionally substituted alkoxy, C₁₋₁₀ optionally substitutedalkenyl or C₁₋₁₀ optionally substituted alkynyl; and R⁸ is —CH₂—, —O—,—S— or —NH—, wherein hydrogen atoms at the 5 (if present), 8, 9 and 14positions respectively are α.α.α.α (i.e., 5α, 8α, 9α, 14α), α.α.α. β,α.α.β.α, α.β.α.α, β.α.α.α, α.α.β.β, α.β.α.β, β.α.α.β, β.α.β.α, β.β.α.α,α.β.β.α, α.β.β.β, β.α.β.β, β.β.α.β, β.β.β.α or β.β.β.β, typicallyα.α.β.α or β.α.β.α.

[0597] 3. The composition of embodiment 2 wherein the one or moreformula 1 compounds has the structure

[0598] hydrogen atoms at the 5 (if present), 8, 9 and 14 positionsrespectively are α.α.α.α, α.α.α.β, α.α.β.α, α.β.α.α, β.α.α.α, α.α.β.β,α.β.α.β, β.α.α.β, β.α.β.α, β.β.α.α, α.β.β.α, α.β.β.β, β.α.β.β, β.β.α.β,β.β.β.α or β.β.β.β, typically α.α.β.α or β.α.β.α.

[0599] 4. The composition of embodiments 1, 2 or 3 wherein one, two,three or four formula 1 compounds are present.

[0600] 5. The composition of embodiments 1, 2, 3 or 4 wherein thecomposition comprises less than about 0.3% v/v water.

[0601] 6. The composition of embodiments 1, 2, 3, 4 or 5 wherein the oneor more nonaqueous liquid excipients is one, two or more of an alcohol,a polyethylene glycol, propylene glycol or benzyl benzoate.

[0602] 7. The composition of any of embodiments 1-6 (embodiment 1, 2, 3,4, 5 or 6) wherein the formula 1 compound is16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-bromo-3β,7β-dihydroxy-5-androstan-17-one,16α-bromo-3β,7β,17β-trihydroxy-5α-androstene,16α-bromo-3β,7α-dihydroxy-5α-androstan-17-one,16α-bromo-3β,7α,17β-trihydroxy-5-androstene,16α-bromo-3β,7β-dihydroxy-5α-androstane,16α-bromo-3β,7β-dihydroxy-5-androstene,16α-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5-androstene,16β-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androsten-17-one,16β-bromo-3β,7β,-dihydroxy-5α-androstan-17-one,16β-bromo-3β,7β,-dihydroxy-5α-androsten-17-one,3β,7α,-dihydroxyepiandrosterone, 3β,7β,-dihydroxyepiandrosterone,3β,-hydroxy-7-oxoepiandrosterone.

[0603] 8. The composition of embodiment 7 wherein the formula 1 compoundis 16α-bromo-3β-hydroxy-5α-androstan-17-one.

[0604] 9. The composition of any of embodiments 1-8 wherein thecomposition comprises two, three, four or five nonaqueous liquidexcipients.

[0605] 10. The composition of embodiment 9 wherein the compositioncomprises three or more nonaqueous liquid excipients.

[0606] 11. The composition of any of embodiments 1-10 wherein theformula 1 compound comprises about 0.0001-99% w/v of the composition.

[0607] 12. The composition of any of embodiments 1-11 wherein thecomposition comprises a unit dose.

[0608] 13. The composition of embodiment 12 wherein the unit dosecomprises about 0.5-100 mg/mL of the formula 1 compound.

[0609] 14. The composition of embodiment 10 wherein the compositioncomprises about 1.0-60 mg/mL of the formula 1 compound.

[0610] 15. The composition of embodiment 14 wherein the formula 1compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-bromo-3β,7β-dihydroxy-5α-androstan-17-one,16α-bromo-3β,7β,17β-trihydroxy-5α-androstene,16α-bromo-3β,7β-dihydroxy-5α-androstane,16α-bromo-3β,7β-dihydroxy-5α-androstene,16α-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstene,16β-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androsten-17-one,16β-bromo-3β,7β,-dihydroxy-5α-androstan-17-one or16β-bromo-3β,7β,-dihydroxy-5α-androsten-17-one.

[0611] 16. The composition of embodiment 1 wherein the one or morenonaqueous liquid excipients comprise a polyethylene glycol, propyleneglycol and benzyl benzoate.

[0612] 17. The composition of embodiment 16 wherein the compositioncomprises less than about 0.3% v/v water.

[0613] 18. The composition of embodiment 17 wherein the formula 1compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-bromo-3β,7β-dihydroxy-5α-androstan-17-one,16α-bromo-3β,7β,17β-trihydroxy-5α-androstene,16α-bromo-3β,7β-dihydroxy-5α-androstane,16α-bromo-3β,7β-dihydroxy-5α-androstene,16α-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstene,16β-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androsten-17-one,16β-bromo-3β,7β,-dihydroxy-5α-androstan-17-one or16β-bromo-3β,7β,-dihydroxy-5α-androsten-17-one.

[0614] 19. The composition of embodiment 18 wherein the formula Icompound is 16a-bromo-3β-hydroxy-5α-androstan-17-one.

[0615] 20. The composition of embodiment 16 that further comprises analcohol.

[0616] 21. The composition of embodiment 20 wherein the formula 1compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-bromo-3β,7β-dihydroxy-5α-androstan-17-one,16α-bromo-3β,7β,17β-trihydroxy-5α-androstene,16α-bromo-3β,7β-dihydroxy-5α-androstane,16α-bromo-3β,7β-dihydroxy-5α-androstene,16α-bromo-3β,7β,17β,-trihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstene,16β-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androsten-17-one,16β-bromo-3β,7β,-dihydroxy-5α-androstan-17-one or16β-bromo-3β,7β,-dihydroxy-5α-androsten-17-one.

[0617] 22. The composition of embodiment 1 wherein the one or morenonaqueous liquid excipients comprise benzyl benzoate, a polyethyleneglycol, an alcohol and optionally an additional nonaqueous liquidexcipient.

[0618] 23. The composition of embodiment 22 wherein the compositioncomprises less than about 0.3% v/v water.

[0619] 24. The composition of embodiment 22 or 23 wherein the formula 1compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-bromo-3β,7β-dihydroxy-5α-androstan-17-one,16α-bromo-3β,7β,17β-trihydroxy-5α-androstene,16α-bromo-3β,7β-dihydroxy-5α-androstane,16α-bromo-3β,7β-dihydroxy-5α-androstene,16α-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstene,16β-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androsten-17-one,16β-bromo-3β,7β,-dihydroxy-5α-androstan-17-one or16β-bromo-3β,7β,-dihydroxy-5α-androsten-17-one.

[0620] 25. The composition of embodiment 24 wherein the formula 1compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one.

[0621] 26. The composition of embodiment 22, 23, 24 or 25 wherein thepolyethylene glycol is polyethylene glycol 300 and/or polyethyleneglycol 200.

[0622] 27. The composition of embodiment 26 wherein the alcohol ispolyethylene glycol is polyethylene glycol 300.

[0623] 28. The composition of embodiments 22 or 23 that comprises about2.5-25% v/v ethanol, about 1-10% v/v benzyl benzoate, about 10-35% v/vpolyethylene glycol 300, about 40-65% v/v propylene glycol and about2-60 mg/mL 16α-bromo-3β-hydroxy-5α-androstan-17-one.

[0624] 28A. The composition of embodiments 22, 23, 24, 25 or 26 thatcomprises about 0.1-10% v/v benzyl benzoate, about 0.1-10% v/v benzylalcohol, about 1-95% v/v polyethylene glycol 200, about 1-95% v/vpropylene glycol and about 2-60 mg/mL16α-bromo-3β-hydroxy-5α-androstan-17-one. The embodiment 28A compositionmay comprise about 2% v/v benzyl benzoate, about 2% v/v benzyl alcohol,about 40% v/v polyethylene glycol 200, about 51 % v/v propylene glycol(qs) and about 50 mg/mL 16α-bromo-3α-hydroxy-5α-androstan-17-one.

[0625] 29. The composition of embodiment 28 that comprises about 12.5%v/v ethanol, about 5% v/v benzyl benzoate, about 25% v/v polyethyleneglycol 300, about 57.5% v/v propylene glycol and about 50 mg/mL16α-bromo-3β-hydroxy-5α-androstan-17-one.

[0626] 30. The composition of any of embodiments 1-29 that furthercomprises a local anesthetic.

[0627] 31. The composition of embodiment 30 wherein the local anestheticis procaine, benzocaine or lidocaine.

[0628] 32. The composition of any of embodiments 1-31 wherein thecomposition comprises a solvate, a suspension, a colloid, a gel or acombination of any of the foregoing.

[0629] 33. A product produced by the process of contacting a compositioncomprising one or more compounds of formula 1 and a first nonaqueousliquid excipient with a second nonaqueous liquid excipient wherein theproduct comprises less than about 3% water and the salts, analogs,configurational isomers and tautomers thereof.

[0630] 34. The product of embodiment 33 wherein the product comprisesless than about 0.3% water.

[0631] 35. The product of embodiments 33 or 34 wherein the firstnonaqueous liquid excipient is a polyethylene glycol (e.g., PEG300 orPEG 200) or propylene glycol.

[0632] 36. The product of embodiments 33, 34 or 35 wherein the secondnonaqueous liquid excipient is a polyethylene glycol (e.g., PEG300 orPEG 200) or propylene glycol.

[0633] 38. A product produced by the process of contacting a compositioncomprising one or more compounds of formula 1 and two nonaqueous liquidexcipients with a third nonaqueous liquid excipient wherein the productcomprises less than about 3% water and the salts, analogs,configurational isomers and tautomers thereof.

[0634] 39. The product of embodiment 38 wherein the product comprisesless than about 0.3% water.

[0635] 40. The product of embodiments 38 or 39 wherein the twononaqueous liquid excipients are selected from a polyethylene glycol(e.g., PEG300 or PEG 200), propylene glycol, benzyl benzoate and analcohol (e.g., ethanol).

[0636] 41. The product of embodiments 38, 39 or 40 wherein the thirdnonaqueous liquid excipient is a polyethylene glycol (e.g., PEG300 orPEG 200), propylene glycol, benzyl benzoate or an alcohol (e.g.,ethanol).

[0637] 42. A product produced by the process of contacting a compositioncomprising one or more compounds of formula I and three nonaqueousliquid excipients with a fourth nonaqueous liquid excipient wherein theproduct comprises less than about 3% water and the salts, analogs,configurational isomers and tautomers thereof.

[0638] 43. The product of embodiment 42 wherein the product comprisesless than about 0.3% water.

[0639] 44. The product of embodiments 42 or 43 wherein the threenonaqueous liquid excipients are selected from a polyethylene glycol(e.g., PEG300 or PEG 200), propylene glycol, benzyl benzoate and analcohol (e.g., ethanol).

[0640] 45. The product of embodiments 42, 43 or 44 wherein the fourthnonaqueous liquid excipient is a polyethylene glycol (e.g., PEG300 orPEG 200), propylene glycol, benzyl benzoate or an alcohol (e.g.,ethanol).

[0641] 46. The product of any of embodiments 33-45 wherein the producthas been stored at reduced temperature (about 4° C. to about 8° C.) orat ambient temperature for about 30 minutes to about 2 years.

[0642] 47. The product of any of embodiments 33-46 wherein the one ormore compounds of formula 1 comprise 1, 2, 3 or 4 formula 1 compounds.

[0643] 48. The product of any of embodiments 33-46 wherein the one ormore compounds of formula 1 comprises one formula 1 compound.

[0644] 49. The product of any of embodiments 33-48 wherein the one ormore formula 1 compound is selected from16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-bromo-3β,7β-dihydroxy-5α-androstan-17-one,16α-bromo-3β,7β,17β-trihydroxy-5α-androstene,16α-bromo-3β,7β-dihydroxy-5α-androstane,16α-bromo-3β,7β-dihydroxy-5α-androstene,16α-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstene,16α-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androsten-17-one,16β-bromo-3β,7β,-dihydroxy-5α-androstan-17-one and16β-bromo-3β,7β,-dihydroxy-5α-androsten-17-one.

[0645] 50. The product of embodiment 49 wherein the formula 1 compoundis 16α-bromo-3β-hydroxy-5α-androstan-17-one.

[0646] 51. The product of embodiment 49 that comprises about 2.5-25% v/vethanol, about 1-10% v/v benzyl benzoate, about 10-35% v/v polyethyleneglycol 300, about 40-65% v/v propylene glycol and about 2-60 mg/mL16α-bromo-3β-hydroxy-5α-androstan-17-one.

[0647] 52. The product of embodiment 51 that comprises about 12.5% v/vethanol, about 5% v/v benzyl benzoate, about 25% v/v polyethylene glycol300, about 57.5% v/v propylene glycol and about 50 mg/mL16α-bromo-3β-hydroxy-5α-androstan-17-one.

[0648] 53. The product of any of embodiments 33-52 that furthercomprises a local anesthetic.

[0649] 54. The composition of 52 wherein the local anesthetic isprocaine, benzocaine or lidocaine.

[0650] 55. A product produced by the process of contacting a compositioncomprising a compound of formula 1 with a nonaqueous liquid excipientwherein the product comprises less than about 3% v/v water and thesalts, analogs, configurational isomers and tautomers thereof.

[0651] 56. The product of embodiment 55 wherein the product comprisesless than about 0.3% v/v water.

[0652] 57. The product of embodiment 53 wherein the product has beenstored at reduced temperature (about 4° C. to about 8° C.) or at ambienttemperature for about 1 hour to about 2 years.

[0653] 58. The product of embodiment 53 wherein the first nonaqueousliquid excipient is a polyethylene glycol, an alcohol, propylene glycolor benzyl benzoate.

[0654] 59. The product of any of embodiments 33-58 wherein the formula 1compound comprises about 0.01 % to about 99% w/v of the product.

[0655] 60. The product of any of embodiments 33-59 wherein the productis a unit dose.

[0656] 61. The unit dose of embodiment 60 comprising a solutioncontaining about 0.5-70 mg/mL of the one or more formula 1 compound.

[0657] 62. The product of any of embodiments 55-61 wherein the one ormore formula 1 compound is selected from16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-bromo-3β,7β-dihydroxy-5α-androstan-17-one,16α-bromo-3β,7β,17β-trihydroxy-5α-androstene,16α-bromo-3β,7β-dihydroxy-5α-and rostane,16α-bromo-3β,7β-dihydroxy-5α-androstene,16α-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstene,16β-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β-hydroxy-5a-androstan-17-one,16β-bromo-3β-hydroxy-5α-androsten-17-one,16β-bromo-3β,7β-dihydroxy-5α-androstan-17-one and16β-bromo-3β,7β,-dihydroxy-5α-androsten-17-one.

[0658] 63. The product of embodiment 62 wherein the formula 1 compoundis 16α-bromo-3β-hydroxy-5α-androstan-17-one.

[0659] 64. The product of any of embodiments 33-61 wherein the one ormore formula 1 compound is selected from the compounds or one or more ofthe species of compounds within the genera named in compound groups 1through 21-10-6.

[0660] 65. A method comprising administering the composition or productof any of embodiments 1-64 to a subject suffering from a pathogeninfection or a malignancy or an immune suppression or disregulationcondition, e.g., a suppressed Th1 immune response or an unwanted Th2immune response.

[0661] 66. The method of embodiment 65 wherein the pathogen infection isa DNA virus infection or an RNA virus infection.

[0662] 67. The method of embodiment 66 wherein the RNA virus infectionis a retrovirus infection or a hepatitis virus infection.

[0663] 68. The method of embodiment 67 wherein the retrovirus infectionor hepatitis virus infection is an HIV, FIV, SIV, SHIV or hepatitis Cvirus infection.

[0664] 69. The method of embodiment 65 wherein the pathogen infection isan intracellular parasite infection.

[0665] 70. The method of embodiment 69 wherein the intracellularparasite infection is a malaria infection.

[0666] 71. The method of embodiment 65 wherein the formula 1 compoundhas the structure

[0667] wherein one, two or three of R⁷, R⁸ and R⁹ are —CH₂— or —CH═ andwherein the configuration of hydrogen atoms at the 5 (if present), 8, 9and 14 positions respectively are α.α.α.α, α.α.α.β, α.α.β.α, β.α.α.α,α.α.β.β, α.β.α.β, β.α.α.β, β.α.β.α, β.β.α.α, α.β.β.α, α.β.β.β, β.α.β.β,β.β.α.β, β.β.β.α or β.β.β.β, typically α.α.β.α or β.α.β.α.

[0668] 72. The method of embodiment 71 wherein the formula 1 compoundhas the structure

[0669] 73. The method of embodiment 72 wherein R¹, R² and R⁴independently are —OH, aC2-C20 ester or C1-C20 alkoxy, R³ is -H and twoor three of R⁷, R⁸ and R⁹ are —CH₂—.

[0670] 74. The method of embodiment 72 or 73 wherein the formula 1compound has the structure

[0671] 75. The method of any of embodiments 71-74 wherein theconfiguration of hydrogen atoms at the 5 (if present), 8, 9 and 14positions respectively are α.α.β.α or β.α.β.α.

[0672] In other embodiments, the fomula 1 compounds include newcompounds, some of which are described in the following numberedembodiments.

[0673] 1A. A compound of formula 1 having the structure

[0674] wherein R⁷, R⁸ and R⁹ are independently selected and wherein one,two or three of R⁷, R⁸ and R⁹ are not —CH₂— or —CH═ and wherein hydrogenatoms at the 5 (if present), 8, 9 and 14 positions respectively are inthe α.α.α.α, α.α.α.β, α.α.β.α, α.β.α.α, β.α.α.α, α.α.β.β, α.β.α.β,β.α.α.β, β.α.β.α, β.β.α.α, α.β.β.α, α.β.β.β, β.α.β.β, β.β.α.β, β.β.β.αor β.β.β.β configurations, typically α.α.β.α or β.α.β.α.

[0675] 2A. The compound of embodiment 1A wherein R⁸ is —CH₂—, —O—, —S—or —NH—.

[0676] 3A. The compound of embodiment 1A or 2A wherein R⁷ is—CH₂—CHR¹⁰—, —O—CHR¹⁰— or —O—C(O)—.

[0677] 4A. The compound of embodiment 1A, 2A or 3A wherein R⁸ or R⁹ isabsent.

[0678] 5A. The compound of embodiment 1A or 2A wherein R⁷ and R⁹independently are —CHR¹⁰—, —CH₂—, —CH═, —O—, —S— or —NH—, wherein R¹⁰ is—OH, —SH, a C₁₋₃₀ organic moiety, a C₁₋₃₀ ester, C₁₋₁₀ optionallysubstituted alkyl, C₁₋₁₀ optionally substituted alkoxy, C₁₋₁₀ optionallysubstituted alkenyl or C₁₋₁₀ optionally substituted alkynyl.

[0679] 6A. The compound of embodiment 1A, 2A, 3A, 4A or 5A wherein theformula 1 compound has the structure

[0680] wherein hydrogen atoms at the 5 (if present), 8, 9 and 14positions respectively are in the α.α.α.α, α.α.α.β, α.α.β.α, α.β.α.α,β.α.α.α, α.α.β.β, α.β.α.β, β.α.α.β, β.α.β.α, β.β.α.α, α.β.β.α, α.β.β.β,β.α.β.β, β.β.α.β, β.β.β.α or β.β.β.β configurations, typically α.α.β.αor β.α.β.α.

[0681] 7A. The compound of embodiment 6A wherein R⁴is —OH, ═O, —SH, aC₁₋₃₀ ester or C₁₋₃₀ alkoxy, wherein the ester or alkoxy moiety isoptionally substituted with one, two or more independently selectedsubstituents, which are optionally selected from —F, —Cl, —Br, —I, —O—,═O, —S—, —NH—, —OR^(PR), —SR^(PR) or NHR^(PR).

[0682] 8A. The compound of embodiment 6A or 7A wherein R¹ is —OH, ═O,—SH, a C₁₋₃₀ ester or C₁₋₃₀ alkoxy, wherein the ester or alkoxy moietyis optionally substituted with one, two or more independently selectedsubstituents, which are optionally selected from —F, —Cl, —Br, —I, —O—,═O, —S—, —NH—, —OR^(PR), —SR^(PR) or —NHR^(PR).

[0683] 9A. The compound of embodiment 1A, 2A or 3A wherein the formula 1compound has the structure

[0684] wherein hydrogen atoms at the 5 (if present), 8, 9 and 14positions respectively are α.α.α.α, α.α.α.β, α.α.β.α, α.β.α.α, β.α.α.α,α.α.β.β, α.β.α.β, β.α.α.β, β.α.β.α, β.β.α.α, α.β.β.α, α.β.β.β, β.α.β.β,β.β.α.β, β.β.β.α or β.β.β.β, typically α.α.β.α or β.α.β.α.

[0685] 10A. The compound of embodiment 9A wherein R⁴ is —OH, ═O, —SH, aC₁₋₃₀ ester or C₁₋₃₀ alkoxy, wherein the ester or alkoxy moiety isoptionally substituted with one, two or more independently selectedsubstituents, which are optionally selected from —F, —Cl, —Br, —I, —O—,═O, —S—, —NH—, —OR^(PR), —SR^(PR) or —NHR^(PR).

[0686] 11A. The compound of embodiment 9A or 10A wherein R¹ is —OH, ═O,—SH, a C₁₋₃₀ ester or C₁₋₃₀ alkoxy, wherein the ester or alkoxy moietyis optionally substituted with one, two or more independently selectedsubstituents, which are optionally selected from —F, —Cl, —Br, —I, —O—,═O, —S—, —NH—, —OR^(PR), —SR^(PR) or —NHR^(PR).

[0687] 12A. A composition comprising a compound of any of embodiments1A-11A and an excipient suitable for human pharmaceutical use or forveterinary use, e.g., an excipient disclosed herein or in the citedreferences.

[0688] 13A. A product produced by the process of contacting a compoundof any of embodiments 1A-11A and an excipient suitable for humanpharmaceutical use or for veterinary use, e.g., an excipient disclosedherein or in the cited references.

[0689] 14A. The use of a compound, composition or product of any ofembodiments embodiments 1A-13A to prepare a medicament for use toprevent or to treat, or to ameliorate one or more symptoms associated,with an infection, an immunesuppression condition, a malignancy, apre-malignant condition or to modulate a mammal's immune response, suchas enhancing a Th1 response or decreasing a Th2 response, e.g., aninfection, malignancy or immune dysregulation as described herein or inthe cited references.

[0690] 15A. The use of embodiment 14A, wherein the infection is a viralinfection (e.g., HIV, HCV, a Herpesvirus, a togavirus, a human papillomavirus infection or other virus described herein or in the citedreferences), a bacterial infection (e.g., Borrelia sp., Legionella sp.or other bacterium described herein or in the cited references), afungal or a yeast infection (e.g., Candida sp., Aspergillus sp. or otheryeast described herein or in the cited references) or a parasiteinfection (e.g., a malaria parasite, a gastrointestinal nematode, ahelminth, Leishmania sp., Cryptosporidium sp., Toxoplasma gondii,Pneumocystis carinii, Schistosoma sp., Strongyloides stercoralis orother parasite described herein or in the cited references).

[0691] 16A. The compound, composition, product or use of any ofembodiments 1A-15A, wherein the formula 1 compound is a compound namedin any of compound groups 1 through 42-25-10-6, or the formula 1compound is a species in any genus described in any of compound groups 1through 42-25-10-6.

[0692] In other aspects, the invention provides dosing methods suitableto treat the conditions described herein. The following embodimentsdescribe some of these methods.

[0693] 1 B. A method comprising intermittently administering one or morecompounds of formula 1 (or a composition comprising a formula 1compound) to a subject or delivering to the subject's tissues a formula1 compound(s) (or a composition comprising a formula 1 compound), e.g.,any formula 1 compound named or described herein, including thecompounds described in embodiments 1-64 and 1A-11A above.

[0694] 2B. The method of embodiment 1 B wherein the subject has aninfection, a hyperproliferation disorder, a hypoproliferation condition,an immunosuppression condition, an unwanted immune response or whereinthe subject has recently experienced or will shortly experience trauma,surgery or a therapeutic treatment wherein the therapeutic treatment isone other than the method of embodiment 1B.

[0695] 3B. The method of embodiment 2B wherein the immunosuppressioncondition or the unwanted immune response is associated with a viralinfection, an intracellular bacterial infection, an extracellularbacterial infection, a fungal infection, a yeast infection, anextracellular parasite infection, an intracellular parasite infection, aprotozoan parasite, a multicellular parasite, an autoimmune disease, acancer, a precancer, a chemotherapy, a radiation therapy, animmunosuppressive therapy, an anti-infective agent therapy, a wound, aburn, the presence of an immunosuppressive molecule, gastrointestinalirritation, or any combination of the foregoing.

[0696] 4B. The method of embodiment 3B wherein the subject'simmunosuppression condition is ameliorated or the unwanted immuneresponse (e.g., a Th2 response) is reduced or wherein the subject's Th1immune response is enhanced.

[0697] 5B. The method of embodiment 3B wherein the subject's innateimmunity, specific immunity or both is enhanced.

[0698] 6B. The method of embodiment 5B wherein the subject's innateimmunity is enhanced.

[0699] 7B. The method of embodiment 6B wherein the subject's specificimmunity is enhanced, e.g., wherein the subject's Th2 immune response isreduced or wherein the subject's Th1 immune reponse is enhanced.

[0700] 8B. The method of embodiment 2B wherein the one or more compoundsof formula 1 is or are administered according to the a dosing regimencomprising the steps,

[0701] (a) administering the one or more compounds of formula 1 to thesubject at least once per day for at least 2 days;

[0702] (b) not administering the one or more formula 1 compounds to thesubject for at least 1 day;

[0703] (c) administering the one or more formula 1 compounds to thesubject at least once per day for at least 2 days; and

[0704] (d) optionally repeating steps (a), (b) and (c) at least once orvariations of steps (a), (b) and (c) at least once.

[0705] 9B. The method of embodiment 8B wherein step (c) comprises thesame dosing regimen as step (a).

[0706] 10B. The method of embodiment 9B wherein step (a) of the dosingregimen comprises administering the one or more formula 1 compounds onceper day, twice per day, three times per day or four times per day.

[0707] 11B. The method of embodiment 10B wherein step (a) of the dosingregimen comprises administering the one or more formula 1 compounds onceper day or twice per day.

[0708] 12B. The method of embodiment 10B wherein step (a) comprisesadministering the one or more formula 1 compounds for about 3 to about24 days.

[0709] 13B. The method of embodiment 12B wherein step (a) comprisesadministering the one or more formula 1 compounds for about 4 to about12 days.

[0710] 14B. The method of embodiment 13B wherein step (a) comprisesadministering the one or more formula 1 compounds for about 4 to about 8days.

[0711] 15B. The method of embodiment 14B wherein step (b) comprises notadministering the one or more formula 1 compounds for about 3 to about120 days.

[0712] 16B. The method of embodiment 15B wherein step (b) comprises notadministering the one or more formula 1 compounds for about 4 to about60 days.

[0713] 17B. The method of embodiment 16B wherein step (b) comprises notadministering the one or more formula 1 compounds for about 5 to about30 days.

[0714] 18B. The method of embodiment 16B wherein step (b) comprises notadministering the one or more formula 1 compounds for about 8 to about60 days.

[0715] 19B. The method of embodiment 15B wherein steps (a), (b), and (c)are repeated at least about 4 times.

[0716] 20B. The method of embodiment 15B wherein steps (a), (b), and (c)are repeated about 5 times to about 25 times.

[0717] 21 B. The method of embodiment 15B wherein steps (a), (b), and(c) and repetitions of steps (a), (b), and (c) occur over a time periodof at least about 2 months.

[0718] 22B. The method of embodiment 15B wherein steps (a), (b), and (c)and repetitions of steps (a), (b), and (c) occur over a time period ofat least about 12 months.

[0719] 23B. The method of embodiment 8B wherein step (b) comprises notadministering the one or more formula 1 compounds for about 3 to about120 days.

[0720] 24B. The method of embodiment 23B wherein step (b) comprises notadministering the one or more formula 1 compounds for about 4 to about60 days.

[0721] 25B. The method of embodiment 24B wherein step (b) comprises notadministering the one or more formula 1 compounds for about 5 to about30 days.

[0722] 26B. The method of embodiment 23B wherein step (b) comprises notadministering the one or more formula 1 compounds for about 8 to about60 days.

[0723] 27B. The method of embodiment 8B wherein step (d) comprisesrepeating steps (a), (b), and (c) at least once.

[0724] 28B. The method of embodiment 27B wherein step (d) comprisesrepeating steps (a), (b), and (c) about 3 times to about 25 times.

[0725] 29B. The method of embodiment 1 B wherein steps (a), (b), and (c)and repetitions of steps (a), (b), and (c) occur over a time period ofat least about 2 months.

[0726] 30B. The method of embodiment 29B wherein steps (a), (b), and (c)and repetitions of steps (a), (b), and (c) occur over a time period ofat least about 12 months.

[0727] 31B. The method of any of embodiments 8B-30B wherein theimmunosuppression condition or the unwanted immune response isassociated with a viral infection, an intracellular bacterial infection,an extracellular bacterial infection, a fungal infection, a yeastinfection, an extracellular parasite infection, an intracellularparasite infection, a protozoan parasite, a multicellular parasite, anautoimmune disease, a cancer, a precancer, a chemotherapy, a radiationtherapy, an immunosuppressive therapy, an anti-infective agent therapy,a wound, a burn, the presence of an immunosuppressive molecule,gastrointestinal irritation or any combination of the foregoing.

[0728] 32B. The method of embodiment 31 B wherein the subject'simmunosuppression condition is ameliorated or the unwanted immuneresponse is reduced.

[0729] 33B. The method of embodiment 32B wherein the subject's innateimmunity, specific immunity or both is enhanced.

[0730] 34B. The method of embodiment 33B wherein the subject's innateimmunity is enhanced.

[0731] 35B. The method of embodiment 34B wherein the subject's specificimmunity is enhanced.

[0732] 36B. The method of embodiment 8B wherein step (c) comprises the ashorter dosing regimen than step (a).

[0733] 37B. The method of embodiment 36B wherein step (a) comprisesadministering the formula 1 compound for 7 to about 24 days.

[0734] 38B. The method of embodiment 37B wherein step (c) comprisesadministering the formula 1 compound for 4 to about 12 days.

[0735] 39B. The method of embodiment 38B wherein step (b) comprises notadministering the formula 1 compound for about 3 to about 120 days.

[0736] 40B. The method of embodiment 39B wherein step (b) comprises notadministering the formula 1 compound for about 4 to about 60 days.

[0737] 41 B. The method of embodiment 40B wherein step (b) comprises notadministering the formula 1 compound for about 5 to about 30 days.

[0738] 42B. The method of embodiment 36B wherein step (d) comprisesrepeating steps (a), (b), and (c) at least once.

[0739] 43B. The method of embodiment 42B wherein step (d) comprisesrepeating steps (a), (b), and (c) about 3 times to about 25 times.

[0740] 44B. The method of embodiment 36B wherein steps (a), (b), and (c)and repetitions of steps (a), (b), and (c) occur over a time period ofat least about 2 months.

[0741] 45B. The method of embodiment 44B wherein steps (a), (b), and (c)and repetitions of steps (a), (b), and (c) occur over a time period ofat least about 12 months.

[0742] 46B. The method of any of embodiments 36B-45B wherein theimmunosuppression condition or the unwanted immune response isassociated with a viral infection, an intracellular bacterial infection,an extracellular bacterial infection, a fungal infection, a yeastinfection, an extracellular parasite infection, an intracellularparasite infection, a protozoan parasite, a multicellular parasite, anautoimmune disease, a cancer, a precancer, a chemotherapy, a radiationtherapy, an immunosuppressive therapy, an anti-infective agent therapy,a wound, a burn, the presence of an immunosuppressive molecule,gastrointestinal irritation or any combination of the foregoing.

[0743] 47B. The method of embodiment 46B wherein the subject'simmunosuppression condition is ameliorated or the unwanted immuneresponse is reduced.

[0744] 48B. The method of embodiment 47B wherein the subject's innateimmunity, specific immunity or both is enhanced.

[0745] 49B. The method of embodiment 48B wherein the subject's innateimmunity is enhanced.

[0746] 50B. The method of embodiment 48B wherein the subject's specificimmunity is enhanced.

[0747] 51 B. The method of embodiment 8B wherein step (c) comprises alonger dosing period than step (a).

[0748] 52B. The method of embodiment 51B wherein step (a) comprisesadministering the formula 1 compound for 7 to about 24 days.

[0749] 53B. The method of embodiment 52B wherein step (c) comprisesadministering the formula 1 compound for 4 to about 12 days.

[0750] 54B. The method of embodiment 53B wherein step (b) comprises notadministering the formula 1 compound for about 3 to about 120 days.

[0751] 55B. The method of embodiment 54B wherein step (b) comprises notadministering the formula 1 compound for about 4 to about 60 days.

[0752] 56B. The method of embodiment 55B wherein step (b) comprises notadministering the formula 1 compound for about 5 to about 30 days.

[0753] 57B. The method of embodiment 51B wherein step (d) comprisesrepeating steps (a), (b), and (c) at least once.

[0754] 58B. The method of embodiment 57B wherein step (d) comprisesrepeating steps (a), (b), and (c) about 3 times to about 25 times.

[0755] 59B. The method of embodiment 51 B wherein steps (a), (b), and(c) and repetitions of steps (a), (b), and (c) occur over a time periodof at least about 2 months.

[0756] 60B. The method of embodiment 59B wherein steps (a), (b), and (c)and repetitions of steps (a), (b), and (c) occur over a time period ofat least about 12 months.

[0757] 61B. The method of any of embodiments 51B-60B wherein theimmunosuppression condition or the unwanted immune response isassociated with a viral infection, an intracellular bacterial infection,an extracellular bacterial infection, a fungal infection, a yeastinfection, an extracellular parasite infection, an intracellularparasite infection, a protozoan parasite, a multicellular parasite, anautoimmune disease, a cancer, a precancer, a chemotherapy, a radiationtherapy, an immunosuppressive therapy, an anti-infective agent therapy,a wound, a burn, the presence of an immunosuppressive molecule,gastrointestinal irritation or any combination of the foregoing.

[0758] 62B. The method of embodiment 61 B wherein the subject'simmunosuppression condition is ameliorated or the unwanted immuneresponse is reduced.

[0759] 63B. The method of embodiment 62B wherein the subject's innateimmunity, specific immunity or both is enhanced or wherein the subject'sTh1 immune reponse is enhanced or the subject's Th2 immune response isdecreased.

[0760] 64B. The method of embodiment 8B wherein the variations of steps(a), (b) and (c) comprise conducting a first dosing regimen of steps(a), (b) and (c) once, twice or three times, followed by one or moresecond dosing regimens of steps (a′), (b′) and (c′) wherein one or moreof the (a′), (b′) and (c′) steps in the second dosing regimen is longerthan the corresponding step in the first dosing regimen.

[0761] 65B. The method of embodiment 8B wherein the variations of steps(a), (b) and (c) comprise conducting a first dosing regimen of steps(a), (b) and (c) once, twice or three times, followed by one or moresecond dosing regimens of steps (a′), (b′) and (c′) wherein one or moreof the (a′), (b′) and (c′) steps in the second dosing regimen is shorterthan the corresponding step in the first dosing regimen.

[0762] 66B. The method of any of embodiments 1B-67B wherein the one ormore formula 1 compounds is or are administered orally, intramuscularly,intravenously, subcutaneously, topically, vaginally, rectally,intracranially, intrathecally, intradermally, as an aerosol or by abuccal route.

[0763] 67B. The method of embodiment 66B wherein the one or more formula1 compounds is or are present in a solid formulation predominantly as asolid or the one or more formula 1 compounds is or are present in aliquid formulation predominantly as a solvate, colloid or a suspensionor the one or more formula 1 compounds is or are present in a gel, creamor paste.

[0764] 68B. The method of any of embodiments 2B-67B wherein thesubject's viral infection, intracellular bacterial infection,extracellular bacterial infection, fungal infection, yeast infection,extracellular parasite infection, intracellular parasite infection,protozoan parasite, multicellular parasite, autoimmune disease, cancer,precancer, chemotherapy, radiation therapy, immunosuppressive therapy,anti-infective agent therapy, a wound, a burn, or the presence of animmunosuppressive molecule, gastrointestinal irritation or anycombination of the foregoing is (a) a DNA virus infection or an RNAvirus infection (HSV, CMV, HBV, HCV, HIV, SHIV, SIV); (b) a mycoplasmainfection, a Listeria infection or a Mycobacterium infection; (c)extracellular bacteria infection; (d) fungal infection; (e) a yeastinfection (Candida, Cryptococcus); (d) protozoa (malaria, leishmania,cryptosporidium, toxoplasmosis, pneumocystis); (e) a multicellularparasite; (f) autoimmune diseases (SLE, RA, diabetes); (g) cancers(solid cancers selected from, e.g., ovarian, breast, prostate, glioma;disseminated cancers selected from lymphoma, leukemia, colon cancer,sarcoma); (h) precancers; (i) chemotherapies (adriamycin, cisplatin,mitomycin C); (j) radiation therapies; (k) immunosuppressive therapies;(I) anti-infective agent therapies; (m) wounds (surgical or otherwise);(n) 1^(st) degree, 2^(nd) degree or 3^(rd) degree burns; (o)immunosuppressive molecules; (p) gastrointestinal irritation (irritablebowel, Crohn's disease, chronic diarrhea); or (q) any combination of (a)through (p).

[0765] 69B. The method of embodiment 68B wherein the RNA virus infectionis a retroviral infection or a hepatitis virus infection.

[0766] 70B. The method of embodiment 68B or 69B wherein the one or moreformula 1 compounds is one formula 1 compound.

[0767] 71 B. The method of embodiment 70B wherein the one or moreformula 1 compounds is or are in a composition that comprises, (a) oneor more nonaqueous liquid excipients, wherein the composition comprisesless than about 3% v/v water; (b) a solid that comprises apharmaceutically acceptable excipient; or (c) one or more liquidexcipients, wherein the composition comprises more than about 3% v/vwater.

[0768] 72B. The method of embodiment 68B or 71 B wherein the formula 1compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-bromo-3β,7β-dihydroxy-5α-androstan-17-one,16α-bromo-3β,7β,17β-trihydroxy-5α-androstene,16α-bromo-3β,7β-dihydroxy-5α-androstane,16α-bromo-3β,7β-dihydroxy-5α-androstene,16α-bromo-3β,7β,17β-trihydroxy-5α-and rostane,16β-bromo-3β,17β-dihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstene,16β-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androsten-17-one,16β-bromo-3β,7β-dihydroxy-5α-androstan-17-one or16β-bromo-3β,7β-dihydroxy-5α-androsten-17-one.

[0769] 73B. The method of embodiment 72B wherein the formula 1 compoundis 16α-bromo-3β-hydroxy-5α-androstan-17-one.

[0770] 74B. The method of embodiments 1B-73B wherein the formula 1compound excludes one or more of any formula 1 compounds.

[0771] 75B. A method to treat involuntary weight loss, oral lesions,skin lesions, opportunistic infections, diarrhea or fatigue in ansubject comprising intermittently administering one or more compounds offormula 1 to the subject (e.g., involuntary weight loss from viralinfection, gastrointestinal infection, chemotherapy, anorexia).

[0772] 76B. The method of embodiment 75B wherein the subject has animmunosuppression condition.

[0773] 77B. The method of embodiment 76B wherein the subject is a human.

[0774] 78B. The method of embodiment 77B wherein the subject is a human1 day to 18 years old (e.g., 1 month to 6 years old).

[0775] 79B. The method of any of embodiments 75B-78B wherein thesubject's specific immunity remains impaired compared to a typicalcomparable control subject who does not have the subject's pathologicalcondition.

[0776] 80B. The method of embodiment 79B wherein the subject's CD4 cellcount does not increase significantly during one or more courses ofdosing (e.g., dosing for 1 week to about 2 weeks or more).

[0777] 81 B. The method of clam 80B wherein the subject's CD4 cell countis about 20 to about 100 CD4⁺ cells/mm³ or about 20 to about 75 CD4⁺cells/mm³.

[0778] 82B. The method of any of embodiments 1B-81B wherein the subjecthas a pathogen(s) infection or a malignancy and the pathogen(s) ormalignancy does not become resistant to the formula 1 compound over atime normally associated with the development of measurable resistancein at least about 50% of subjects who are treated with a therapeutictreatment(s) other than a formula 1 compound(s).

[0779] 83B. The method of embodiment 82B wherein the pathogen infectionis an HIV, SIV, SHIV or HCV infection.

[0780] 84B. The method of embodiments 82B or 83B wherein the formula 1compound is one or more of 16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-bromo-3β,7β-dihydroxy-5α-androstan-17-one,16α-bromo-3β,7β,17β-trihydroxy-5α-androstene,16α-bromo-3β,7β-dihydroxy-5α-androstane,16α-bromo-3β,7β-dihydroxy-5α-androstene,16α-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstane,16β-bromo-3β,17β-dihydroxy-5α-androstene,16β-bromo-3β,7β,17β-trihydroxy-5α-androstane,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androsten-17-one,16β-bromo-3β,7β,-dihydroxy-5α-androstan-17-one,16β-bromo-3β,7β,-dihydroxy-5α-androsten-17-one or a physiologicallyacceptable ester, carbonate, carbamate, amino acid conjugate or peptideconjugate thereof.

[0781] 85B. The method of embodiment 84B wherein the formula 1 compoundis 16α-bromo-3β-hydroxy-5α-androstan-17-one or a physiologicallyacceptable ester, carbonate, carbamate, amino acid conjugate or peptideconjugate thereof.

[0782] 86B. The method of any of embodiments 1B-85B, wherein the formula1 compound is a compound named in any of compound groups 1 through42-25-10-6, or the formula 1 compound is a species in any genusdescribed in any of compound groups 1 through 42-25-10-6.

[0783] In other embodiments, the invention provides methods to modulateimmune cells or immune responses in a subject. The following numberedembodiments describe some of these methods.

[0784] 1 C. A method to modulate a subject's innate immunity or toenhance a subject's Th1 immune response or to reduce a subject's Th2immune responses comprising administering to the subject a compound(s)of formula 1, including any formula 1 compound that is described ordisclosed herein, including the compounds described in embodiments 1-64and 1A-1 1A above.

[0785] 2C. The method of embodiment 1C wherein the subject's innateimmunity is enhanced.

[0786] 3C. The method of embodiment 1 C or 2C wherein the subjectsuffers from an innate immunity suppression condition, a suppressed Th1immune response or an unwanted Th2 immune response.

[0787] 4C. The method of embodiment 3C wherein the innate immunitysuppression condition, the suppressed Th1 immune response or theunwanted Th2 response is associated with a viral infection, anintracellular bacterial infection, an extracellular bacterial infection,a fungal infection, a yeast infection, an extracellular parasiteinfection, an intracellular parasite infection, a protozoan parasite, amulticellular parasite, an autoimmune disease, a cancer, a precancer, achemotherapy, a radiation therapy, an immunosuppressive therapy, ananti-infective agent therapy, a wound, a burn, the presence of animmunosuppressive molecule or any combination of the foregoing.

[0788] 5C. The method of any of embodiments 1C-3C wherein the subject'sTh1 immune response is enhanced.

[0789] 6C. The method of embodiment 1C wherein the subject's Th2 immuneresponse is reduced.

[0790] 7C. The method of embodiment 6C wherein the subject has acondition comprising an unwanted immune response (e.g., autoimmunedisease, SLE, diabetes).

[0791] 9C. The method of embodiment 6C or 7C wherein the subject is avertebrate, a mammal, a primate or a human.

[0792] 10C. The method of embodiment 9 wherein the vertebrate's, themammal's the primate's or the human's specific immunity modulation is(i) an enhanced CTL or Th1 response to a virus infection or to amalignant cell in vitro or in vivo, (ii) enhanced antigen presentationor biological activity by dendritic cells or dendritic cell precursors,or (iii) enhanced killing of virus-infected or of malignant cells.

[0793] 11 C. The method of 10C wherein the vertebrate is a human, thevirus infection is an HIV infection and the CTL or Th1 responsecomprises an enhanced response to one or more of the HIV's gag proteinor to the HIV's gp120.

[0794] 12C. The method of embodiment 1C, 4C,10C or 11C wherein thesubject's Th1 cells, tumor-infiltrating lymphocytes (TIL cells), NKcells, peripheral blood lymphocytes, phagocytes, monocytes, macrophage,neutrophils, eosinophils, dendritic cells or fibrocytes are activated asmeasured by, e.g., enhanced ³H-thymidine uptake compared to untreatedcontrols or by an increase in the number of the cell type in circulationor demonstrable movement of the cell type from one tissue or compartment(e.g., skin) to another tissue or compartment (e.g., blood, lymph node,spleen or thymus).

[0795] 13C. The method of embodiment 1C, 4C,10C, 11 C or 12C, whereinthe formula 1 compound(s) modulates transcription of one or more genesin the subject's NK cells, phagocytes, monocytes, macrophages,neutrophils, eosinophils, dendritic cells or fibrocytes are activated(e.g., as measured by increased protein kinase C activity or bymodulation of a biological activity of a steroid receptor or an orphannuclear hormone receptor).

[0796] 14C. The method of embodiment 1C wherein the formula 1compound(s) enhances lysosome movement in one or more of the subject'sNK cells, phagocytes, monocytes, macrophages, neutrophils, eosinophils,dendritic cells or fibrocytes.

[0797] 15C. The method of embodiment 1C wherein the formula 1compound(s) enhances protein kinase C activity in one or more of thesubject's NK cells, phagocytes, monocytes, macrophages, neutrophils,eosinophils, dendritic cells or fibrocytes (e.g., PKCα, PKCβ, PKCγ andPKCζ).

[0798] 16C. A composition comprising a partially purified or a purifiedcomplex comprising a formula 1 compound and a steroid receptor, a serumsteroid-binding protein (e.g., human serum albumin, α1-acidglycoprotein, sex hormone-binding globulin, testosterone-bindingglobulin, corticosteroid-binding globulin, androgen binding protein(rat)) or a binding partner (e.g., complexing agent, liposome,antibody).

[0799] 17C. A product produced by the process of contacting thepartially purified or the purified composition of embodiment 16C withone or more sterile containers, one or more syringes, one or morepharmaceutically acceptable excipients (e.g., excipient as defined indraft spec above and including sugars, lactose, sucrose, fillers,lubricants, binders, or any excipient named in any reference citedherein), one or more cells, one or more tissues, plasma or blood.

[0800] 18C. The method of any of embodiments 1C-17C wherein the subjecthas an infection, a hyperproliferation disorder, a hypoproliferationcondition, an immunosuppression condition, an unwanted immune responseor wherein the subject has recently experienced or will shortlyexperience trauma, surgery or a therapeutic treatment wherein thetherapeutic treatment is one other than the method of embodiment 1C.

[0801] 19C. The method of embodiment 18C wherein the immunosuppressioncondition or the unwanted immune response is associated with a viralinfection, an intracellular bacterial infection, an extracellularbacterial infection, a fungal infection, a yeast infection, anextracellular parasite infection, an intracellular parasite infection, aprotozoan parasite, a multicellular parasite, an autoimmune disease, acancer, a precancer, a chemotherapy, a radiation therapy, animmunosuppressive therapy, an anti-infective agent therapy, a wound, aburn, the presence of an immunosuppressive molecule, gastrointestinalirritation, or any combination of the foregoing.

[0802] 20C. The method of embodiment 19C wherein the subject'simmunosuppression condition is ameliorated or the unwanted immuneresponse is reduced.

[0803] 21C. The method of embodiment 19C wherein the subject'simmunosuppression condition is associated with a viral infection.

[0804] 22C. The method of embodiment 21C wherein the viral infectioncomprises a DNA virus or an RNA virus infection.

[0805] 23C. The method of embodiment 22C wherein the RNA virus infectioncomprises a retroviral infection or a hepatitis virus infection.

[0806] 24C. The method of any of embodiments 18C-23C wherein the subjectsuffers from one or more of chronic diarrhea, involuntary weight loss(usually at least about 5% or more), cachexia (usually at least about 5%or more), muscle wasting, one or more oral lesions (usually at leastabout 1 cm²), one or more genital lesions (usually at least about 1cm²), skin lesions (usually at least about 1 cm²) or an opportunisticinfection associated with AIDS.

[0807] 25C. A method (e.g., to determine a biological activity of aformula 1 compound or to modulate transcription of a gene in a cell orcell-free transcription system) comprising: (a) contacting the formula 1compound(s) with a cell or cell population in vitro or in vivo; (b)measuring one or more of (i) a complex between a binding partner and theformula 1 compound, (ii) proliferation of the cell or cell population,(iii) differentiation of the cell or cell population (iv) an activity ofa protein kinase C, (v) a level of phosphorylation of a protein kinase Csubstrate, (vi) transcription of one or more target genes, (vii)enhancement or inhibition of the cellular response to steroids, e.g.,glucocorticoids, (viii) inhibition of steroid-induced transcription,e.g., glucocorticoids, sex steroids, (ix) inhibition of retrovirus(e.g., HIV, SIV, FIV or SHIV) LTR-driven transcription, or (x)modulation of the numbers of an immune cell population in circulation invivo (e.g., circulating peripheral blood lymphocytes in a mammal such asa primate or a human); and (c) optionally comparing the result obtainedin step (b) with an appropriate control.

[0808] 26C. The method of embodiment 25C wherein the binding partner isa steroid receptor, a transcription factor or a steroid hormonesuperfamily orphan receptor.

[0809] 27C. The method of embodiment 25C wherein the biological activitydetermined is a modulating activity of the formula 1 compound forreplication or cytopathic effects associated with a retrovirus, ahepatitis virus or a protozoan parasite.

[0810] 28C. The method of embodiment 25C wherein the biological activitydetermined is a modulating activity of the formula 1 compound forreplication, cytopathic effects associated with the retrovirus, thehepatitis virus or the protozoan parasite or the biological activitydetermined is metabolism (assay by ³H-thymidine uptake) of a cell orcell population comprising NK cells, phagocytes, monocytes, macrophages,basophils, eosinophils, fibrocytes, transformed cells, virus-infectedcells, bacteria-infected cells or parasite-infected cells.

[0811] 29C. The method of embodiment 25C wherein the target gene is avirus gene, a bacterial gene, a parasite gene, a gene associated withcancer.

[0812] 30C. The method of embodiment 29C wherein the virus gene is apolymerase gene, a reverse transcriptase gene, an envelope gene, aprotease gene or a gene associated with viral nucleic acid replicationor a viral structural gene.

[0813] 31C. The method of embodiment 30C wherein the polymerase geneencodes a DNA polymerase or encodes an RNA polymerase.

[0814] 32C. The method of embodiment 30C wherein the reversetranscriptase gene encodes a human, primate, avian or feline retrovirusreverse transcriptase.

[0815] 33C. A method comprising administering a compound(s) of formula 1to a human or primate who has a retroviral infection and a CD4 count of550 or less.

[0816] 34C. The method of embodiment 33C wherein the human has a CD4count of about 20 to about 100 or about 20 to about 80.

[0817] 35C. The method of embodiment 33C wherein the human has a CD4count of about 30 to about 150.

[0818] 36C. The method of embodiment 33C wherein the human has a CD4count of about 500 or less, about 450 or less, about 400 or less, about350 or less, about 300 or less, about 250 or less, about 200 or less,about 150 or less, about 100 or less, about 50 or less or about 25 orless or about 20 or less.

[0819] 37C. The method of any of embodiments 33C-36C wherein the formula1 compound(s) is present in a composition that comprises one or morenonaqueous liquid excipients and less than about 3% v/v water or any ofthe formulations as disclosed in the specification or any of thenumbered embodiments above.

[0820] 38C. The method of any of embodiments 33C-37C wherein the formula1 compound(s) is administered according to an intermittent dosingprotocol as disclosed in the specification or any of the numberedembodiments above.

[0821] 39C. The method of any of embodiments 30C-45C wherein the humanis coinfected with hepatitis C virus, hepatitis B virus, HSV-1, HSV-2, amalaria parasite, a Pneumocystis parasite, or a Cryptosporidiumparasite.

[0822] 40C. The method of embodiment 46C wherein level of the HCV isreduced in the human.

[0823] 41C. A method comprising administering a formula 1 compound(s) toa subject, or to a nervous system cell(s) in tissue culture whereby theformula 1 compound(s) binds to a receptor associated with a cell(s) inthe nervous system and (1) elicits a biological response in the cell(s)in the nervous system or in the cell(s) in tissue culture and/or (2)elicits a neuronal response that is transmitted to a distant site(s) orcell(s) where the method optionally is used to screen a formula 1compound(s) for its biological activity, to treat a pathologicalcondition (e.g., pathogen infection such as a virus (HIV), a malignancyor a neurological disorder, e.g., AIDS associated dementia, Alzheimer's,Parkinson's, Multiple Sclerosis) in the subject or to determine thebioavailability or metabolism of the formula 1 compound(s) to thesubject or the cell(s) in the nervous system or in tissue culture,wherein metabolism is optionally determined by comparing the biologicaleffect of a formula 1 compound(s) with a control compound, which can bea different formula 1 compound.

[0824] 42C. The method of embodiment 41 wherein the receptor associatedwith the cell in the nervous system is a neurotransmitter receptor(s)(e.g., a γ-aminobutyric acid receptor such as type A, a NMDA receptor)and/or a steroid receptor (e.g., androgen receptor, estrogen receptor).

[0825] 43C. The method of embodiment 41C or 42C wherein the cell(s) inthe nervous system is a neuron(s), and astrocyte(s) and/or a glialcell(s).

[0826] 44C. The method of embodiment 41C, 42C or 43C wherein thebiological response in the cell(s) in the nervous system or in thecell(s) in tissue culture is increased or decreased transcription of agene(s) (e.g., a neurotransmitter, vasopressin, a heat shock protein),increased or decreased secretion of a protein(s) (e.g., vasopressin),reduced damage from oxidative stress, enhanced nitric oxide releaseand/or enhanced neurite growth.

[0827] 45C. The method of any of embodiments 1C-44C wherein thecompound(s) of formula 1 is any one or more formula 1 compound selectedfrom the compounds or one or more of the species of compounds within thegenera named in compound groups 1 through 21-10-6.

[0828] 46C. A method to (a) modulate the expression of at least oneimmune cell antigen by an immune cell in a subject, wherein the immunecell antigen is selected from CD3, CD11 c, CD14, CD16, CD19, CD25, CD38,CD56, CD62L, CD69, CD45RA, CD45RO, CD123, HLA-DR, IL-1, IL-2, IL-4,IL-6, IL-8, IL-10, TNFα, IGF, and γIFN, or (b) activate CD8⁺ T cells orCD8⁻ T cells in a subject, wherein the activation comprises at leasttransiently enhanced expression of CD25 or CD69 by the T cells, or (c)increase the proportion of CD8⁺ or CD8⁻ lymphokine activated killercells in a subject's CD16+ cells (e.g., CD8⁺, CD16⁺, CD38⁺ or cellsCD8-, CD1 6+, CD38+), or (d) increase the proportion of (i) CD8⁻, CD16⁺natural killer cells, (ii) CD8⁺, CD16⁺ natural killer cells or (iii)CD8⁻, CD16⁺ cells that mediate antibody-dependent cell-mediatedcytotoxicity, or (iv) CD8⁺, CD16⁺ cells that mediate antibody-dependentcell-mediated cytotoxicity, or (e) increase the proportion of dendriticcell precursors in a subject's circulating white blood cells (e.g.,Lin⁻, HLA-DR⁺, CD123⁺ or Lin⁻ HLA-DR⁺, CD11c⁺ cells) or (f) increase theproportion of CD45RA⁺ T cells or CD45⁺, RO⁺ T cells in a subject'scirculating white blood cells, or (g) change (increase or decrease) theproportion or relative numbers of CD62L⁺ T cells in a subject'scirculating white blood cells, or (h) increase the proportion of CD8⁺ orCD4⁺ T cells that express CD62L in a subject's circulating CD8⁺ or CD4⁺T cells, or (i) decrease the proportion of CD8⁺ or CD4⁺ T cells thatexpress CD62L in a subject's circulating CD8⁺ or CD4⁺ T cells, or (j)increase the proportion of HLA-DR⁺, CD8⁺, CD38⁺ cells in a subject'scirculating white blood cells, or (k) decrease the level of IL-4 orIL-10 that is expressed by or present in a subject's white blood cellsor in a subject's plasma (or that is expressed after the subject's whitecells are stimulated in vitro), (I) at least transiently increase thenumber of dendritic cell precursors or dendritic cells that are presentin a subject's white blood cells or in a subject's plasma, or (m)enhance the capacity of CD4⁺ T cells to express IL-2, IL-1 2 or γIFN,the method comprising administering to the subject a formula 1 compoundand a pharmaceutically acceptable excipient.

[0829] 47C. The method of embodiment 46C wherein formula 1 has thestructure

[0830] wherein R¹ is —OH or a group (e.g., a C1-30 ester) that canhydrolytically convert under physiological conditions to —OH, either ofwhich may be in the α- or β-configuration; R² is hydrogen in the α- orβ-configuration, or R² is absent when there is a double bond at the 5-6position; R³ is —H or —Br, either of which may be in the α- orβ-configuration; R⁴ is —OH or a group (e.g., a C1-30 ester) that canhydrolytically convert under physiological conditions to —OH, either ofwhich may be in the α- or β-configuration, or R⁴ is ═O and the hydrogenatom bonded to the same carbon is absent; R^(4A) is R⁴, —C(O)—CH³ or—C(O)—(CH₂)₁₋₆—CH³; R⁵ is —H or —OH or a group (e.g., a C1-30 ester)that can hydrolytically convert under physiological conditions to —OH,either of which may be in the α- or β-configuration, or R⁵ is ═O and thehydrogen atom bonded to the same carbon is absent; and the dotted lineat the 5-6 position is an optional double bond, or wherein the formula 1compound has the structure shown in any formula 1 compound named ordescribed herein, including the compounds described in embodiments 1-64and 1A-11A above.

[0831] 48C. The method of embodiment 46C or 47C wherein the formula 1compound is administered to the subject daily over a period from one toabout 15 days, e.g., for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15 or more days.

[0832] 49C. The method of embodiment 48C wherein the expression of theimmune cell antigen is detectably modulated for at least about 4-7 daysafter the last administration of the formula 1 compound to the subject,e.g., for at least 4, 5, 6, 7 or more days.

[0833] 50C. The method of embodiment 48C or 49C wherein the expressionof the immune cell antigen is detectable at least about 8-90 days afterthe last administration of the formula 1 compound, e.g., for at leastabout 8, 10, 12, 15, 20, 25, 28, 30, 35, 40, 42, 45, 49, 50, 55, 56, 60,63, 65, 70, 75, 77, 80, 84, 85, 90, 91 95, 98, 100 or more days.

[0834] 51C. The method of any of embodiments 46C-51 C wherein thesubject has an immunosuppression condition, a pathogen infection or aconditions associated with a deficient Th1 immune reponse or anexcessive Th2 immune response.

[0835] 52C. The method of embodiment 51 C wherein the pathogen infectionis a viral infection, a bacterial infection, a yeast infection, a fungalinfection or a viroid infection, e.g., wherein the pathogen infection isa viral infection such as a DNA virus infection or an RNA virusinfection (e.g., an infection caused by a Hepadnavirus, a Parvovirus, aPapovavirus, an Adenovirus, a Herpesvirus, Retrovirus, a Flavivirus, aTogavirus, a Rhabdovirus, a Picornavirus, a Bunyavirus, a Reovirus, anOrthomyxovirus or a Paramyxovirus, such as a HIV1, HIV2, SIV, SHIV oranother virus described herein or in the cited references).

[0836] 53C. The method of embodiment 52C wherein the subject has animmunosuppression condition that is associated with or caused by apathogen infection.

[0837] 54C. The method of any of embodiments 46C-53C wherein the subjectis a mammal, a human, a primate or a rodent.

[0838] 55C. The method of any of embodiments 46C-54C wherein about 0.05mg/kg/day to about 20 mg/kg/day is administered parenterally (e.g., byintravenous, subcutaneous, intramuscular, or intramedullary injection),topically, orally, sublingually or bucally to the subject, e.g., about0.1 mg/kg/day, about 0.2 mg/kg/day, about 0.5 mg/kg/day, about 1.0mg/kg/day, about 1.5 mg/kg/day, about 2 mg/kg/day, about 2.5 mg/kg/day,about 3.0 mg/kg/day, about 4 mg/kg/day or about 6 mg/kg/day, i.e., about0.1-10 mg/kg/day, typically about 0.2-7 mg/kg/day.

[0839] 56C. The method of embodiment 55C wherein the subject isconcurrently taking one or more second therapeutic agents to treat apathogen infection, e.g., a viral infection, such as a HIV-1 infection,a HIV-2 infection, a HAV infection, a HBV infection, a HCV infection, anEpstein Barr virus infection, a HSV-1 infection, a HSV-2 infection,human herpesvirus 6 infection, human herpesvirus 7 infection, humanherpesvirus 8 infection, or a bacterial infection or a parasiteinfection, such as a malaria infection, leishmaniasis,cryptosporidiosis, toxoplasmosis, a mycoplasma infection, a Trichomonasinfection, a Chlamidya infection, a Pneumocystis infection, a Salmonellainfection, a Listeria infection, an Escherichia coli infection, aYersinia infection, a Vibrio infection, a Pseudomonas infection, aMycobacterium infection, a Haemophilus infection, a Neisseria infection,a Staphylococcus infection or a Streptococcus infection.

[0840] 57C. The method of embodiment 56C wherein the one or more secondtherapeutic agents is a protease inhibitor, a reverse transcriptaseinhibitor, a viral, bacterial or parasite DNA or RNA polymeraseinhibitor, an antibacterial antibiotic or an antifungal agent, such asAZT, ddl, ddC, D4T, 3TC, a viral (e.g., HIV) fusion inhibitor,hydroxyurea, nelfinavir, saquinavir, ritonavir, indinavir, chloroquine,a chloroquine analog, amphotericin B, fluconazole, clotrimazole,isoniazid, dapsone, rifampin, cycloserine, erythromycin, a tetracyclineantibiotic, vancomycin, ethambutol, pyrazinamide, a flurorquinolone(e.g., ciprofloxacin, norfloxacin), a cephalosporin antibiotic, aβ-lactam antibiotic or an aminoglycoside antoibiotic (e.g.,streptomycin, kanamycin, tobramycin).

[0841] 58C. The method of any of embodiments 46C-57C wherein the subjectis a human, a primate, a canine, a feline or a rodent.

[0842] 59C. A composition comprising an effective amount of an immunecell subset modulatory compound of formula 1 and a pharmaceuticallyacceptable carrier.

[0843] 60C. The composition of embodiment 59C wherein the immune cellsubset is (1) CD8⁺ T cells, (2) CD4⁺ T cells, (3) CD8⁺ lymphokineactivated killer cells, (4) CD8⁻ lymphokine activated killer cells, (5)CD8⁻, CD16⁺ natural killer cells, (6) CD8⁺, CD16⁺ natural killer cells,(7) CD8⁻, CD16⁺ cells that mediate antibody-dependent cell-mediatedcytotoxicity, (8) CD8⁺, CD16⁺ cells that mediate antibody-dependentcell-mediated cytotoxicity, (9) dendritic cells or dendritic cellprecursors, (10) CD45RA⁺ T cells, (11) CD45RO⁺ T cells, (12) CD45RA⁺,CD45RO⁺ T cells, (13) CD8⁺, CD62L T cells, (11) CD4⁺, CD62L⁺ T cells or(14) HLA-DR⁺, CD8⁺, CD38⁺ T cells.

[0844] 61C. A method to detect a biological response associated with theadministration of a compound of formula 1 to a subject comprising (1)obtaining a sample from the subject, (2) administering the compound offormula 1 to the subject to obtain a treated subject (3) obtaining asecond sample from the treated subject, (4) within 24 hours of obtainingthe sample, analyzing the sample to obtain control information fordetecting the biological response, (5) within 24 hours of obtaining thesecond sample, analyzing the second sample for the presence or absenceof a biological response to obtain experimental information and (6)optionally comparing the control information with the experimentalinformation to detect the presence, absence, relative magnitude orabsolute magnitude of the biological response

[0845] 62C. The method of embodiment 61C wherein the compound of formula1 further comprises a pharmaceutically acceptable carrier.

[0846] 63C. The method of embodiment 61C or 62C wherein the biologicalresponse associated with the administration of the compound of formula 1to the subject is modulation of the expression of a cell surfaceantigen, an increased absolute or relative number of cells in an immunecell subset, a decreased absolute or relative number of cells in animmune cell subset or an unchanged absolute or relative number of cellsin an immune cell subset.

[0847] 64C. The method of embodiment 63C wherein the immune cell subsetis CD8⁺ T cells, CD4⁺ T cells, CD8⁺ lymphokine activated killer cells,CD8⁻, CD16⁺ natural killer cells, circulating dendritic cell precursors,circulating dendritic cells, tissue dendritic cell precursors, tissuedendritic cells, CD8⁺ lymphokine activated killer cells, CD8⁻ lymphokineactivated killer cells, CD8⁻, CD16⁺ natural killer cells, CD8⁺, CD16⁺natural killer cells, CD8⁻, CD16⁺ cells that mediate antibody-dependentcell-mediated cytotoxicity, CD8⁺, CD16⁺ cells that mediateantibody-dependent cell-mediated cytotoxicity, CD45RA⁺ T cells, CD45RA⁺,CD45RO⁺ T cells, CD45RO⁺ T cells, CD8⁺, CD62L T cells, CD4⁺, CD62L⁺ Tcells or HLA-DR⁺, CD8⁺, CD38⁺ T cells, monocytes or macrophages.

[0848] 65C. The method of embodiment 64C wherein the biological responseis at least transient modulation of an immune cell antigen or an immuneaccessory cell antigen (e.g., an adhesion molecule at the surface ofendothelial cells or a cytokine receptor at the surface of T cells or Bcells).

[0849] 66C. The method of embodiment 65C wherein the immune cell antigenis a protein, glycoprotein or cell surface antigen usually or onlyexpressed by lymphoid cells (lymphocytes or white blood cells or theirprecursors, e.g., T cells, B cells, monocytes, macrophage, LAK cells, NKcells, dendritic cells).

[0850] 67C. The method of embodiment 65C wherein the immune cell antigenis a CD molecule, an interleukin or a cytokine, optionally selected fromCD16, CD25, CD38, CD62L, CD69, CD45RA, CD45RO, IL-1, IL-2, IL-4, IL-6,IL-8, IL-10, TNFα, IGF₁ and γIFN.

[0851] 68C. The method of any of embodiments 61C-67C wherein the subjectis a human, a primate, a canine, a feline or a rodent.

[0852] 69C. A method to alter the Th1-Th2 balance in a subjectcomprising administering an effective amount a compound of formula 1 toa subject whereby the subject's expression or secretion of IL-4 or IL-10is detectably modulated.

[0853] 70C. The method of embodiment 30 wherein the subject's expressionor secretion of IL-4 or IL-10 is decreased and the Th1-Th2 balance inthe subject's Th1 immune responses to an infection or immunosuppressioncondition is detectably enhanced.

[0854] 71C. The method of any of embodiments 1C-70C, wherein the formula1 compound is a compound named in any of compound groups 1 through42-25-10-6, or the formula 1 compound is a species in any genusdecsribed in any of compound groups 1 through 42-25-10-6.

[0855] Variations and modifications of these embodiments, the claims andthe remaining portions of this disclosure will be apparent to theskilled artisan after a reading thereof. Such variations andmodifications are within the scope and spirit of this invention. Allcitations herein are incorporated herein by reference in their entirety.All citations herein are incorporated herein by reference withspecificity.

EXAMPLES

[0856] The following examples further illustrate the invention and theyare not intended to limit it in any way.

Example 1 BrEA Formulation

[0857] Two lots of a non-aqueous BrEA formulation were made at a BrEAconcentration of 50 mg/mL in 25% polyethylene glycol 300, 12.5%dehydrated ethyl alcohol, 5% benzyl benzoate, and 57.5% propylene glycolas follows. BrEA was obtained from Procyte, Inc. The remainingexcipients are shown below. Specifi- Supplier Final Product Excipientcation Lot No. Concentration Propylene glycol USP Arco Chemical 57.5%(v:v) HOC-61220-01104 Polyethylene glycol NF Union Carbide   25% (v:v)300 695752 Dehydrated alcohol USP McCormick Distilling 12.5% (v:v) 97K10Benzyl benzoate USP Spectrum   5% (v:v) Pharmaceuticals MG025

[0858] The formulation was prepared by suspending BrEA in polyethyleneglycol 300, and sequentially adding propylene glycol, benzyl benzoate,and dehydrated ethyl alcohol to form a solution, which was diluted tothe final desired volume with additional propylene glycol. The procedureis described below.

[0859] The calculated amount of polyethylene glycol 300 was added to acompounding vessel. Then, while mixing, the calculated amount of BrEAwas added to the vessel, and mixed for at least 5 minutes to form asmooth, creamy liquid propylene glycol was added to the vessel, andmixed for a minimum of 5 minutes to form a uniform suspension. Thecalculated amount of benzyl benzoate is added to the vessel, and mixedfor approximately 5 minutes to form a translucent liquid suspension.Dehydrated alcohol was added to the vessel, and mixed for approximately5 minutes to form a clear, colorless solution. Propylene glycol was thenadded to achieve the desired final formulation, and mixed forapproximately 5 minutes. The drug solution was transferred to avolume-dispensing device set to deliver 1.2 mL per vial. Under nitrogenpressure, the solution was filtered through two 0.2 μm polyvinylidenefluoride filters in series into 2 cc amber glass vials. The vials werecapped with Teflon-coated, butyl-rubber stoppers and crimp sealed.Materials used in the product vials are listed below. Material SourceProduct Code Description Vial Wheaton 2702-B51BA Tubing vial, 2 mL/13mm, glass, type 1 amber Stopper Omniflex V9239 FM257/2 13 mm, Tefloncoated, butyl rubber stopper Seal West 4107 Flip seal, 13 mm, mist graybridge

[0860] Product specifications were examined by one or more of thefollowing assays. Test Specification Method Physical Examination Clearcolorless solution with slight alcoholic odor Volume recovery NLT* 1.0mL USP23<1> Specific gravity TBD USP23<841> Assay for active component90-110% of label HPLC Sterility sterile USP23<71> Endotoxin <0.1 EU/mgUSP23<85> Particulate matter ≧10 μm NMT** 6000/cnt USP23<788> ≧25 μm NMT600/cnt

[0861] Lot Analysis Test Specification Lot 1 Lot 2 Physical Clearcolorless solution Positive Positive Examination with slight alcoholicodor Volume recovery NLT 1.0 mL 1.15 mL — Specific gravity TBD 1.0411 —Assay for active 90-110% of label 103.10% 104.25% component Sterilitysterile sterile — Endotoxin <0.1 EU/mg 0.024 EU/mg — Particulate matter≧10 μm NMT 6000/cnt 26 — ≧25 μm NMT 600/cnt 15

Example 2 BrEA Drug Substance and BrEA Formulation Stability

[0862] An accelerated stability study of 6 months duration is conductedusing BrEA and the formulations from example 1. Samples are taken at 1,2, 3, 4, 5, and 6 month time points and compared with the specificationslisted in example 1. Real time stability (25° C., 60% relative humidity)is conducted using BrEA formulation Lots 1 and 2, with sampling timepoints at 3, 6, 9, 12, 18, 24, and 36 months. After 3 months of storageat 40° C. and 75% relative humidity, the assay potency of BrEA is atleast 95% of the label value. The results from the stability testingindicate that BrEA is stable for at least 3 months at elevatedtemperature and humidity in the Lot 1 and 2 formulations.

Example 3 Primate Intermittent Dosing Protocol

[0863] Pig-tail Macaque monkeys infected with the SHIV₂₂₉ retroviruswere treated with a BrEA formulation as described in example 1. SHIV₂₂₉is a recombinant retrovirus containing HIV and SIV sequences. J.Thompson et al., abstract #75, 16^(th) Annual Symposium on NonhumanPrimate Models for AIDS, Oct. 7-10, 1998, Atlanta, Ga., M. Agy et al.,abstract #67, 16^(th) Annual Symposium on Nonhuman Primate Models forAIDS, Oct. 7-10, 1998, Atlanta, Ga. In monkeys, it establishes anaggressive infection that leads to severe symptoms of end-stage diseasein infected untreated animals at about 180-210 days after infection.Four pig-tail macaques (2/group) received subcutaneous injections of theformulation at 1 or 2 mg/kg body weight for 10 consecutive days(Protocol 1). On week 8, 3 of the 4 monkeys were retreated and 2treatment naive monkeys were treated with 5 mg/kg of the formulation onan every other day basis for a period of 20 days (Protocol 2). On week19, all primates receiving treatment began a 3 course treatment regimenwith 3 mg/kg the BrEA formulation once daily for 10 consecutive days,repeated every four weeks for a total of 3 treatment courses (Protocol3).

[0864] The animals were infected with 1-100 TCID₅₀ units administeredintravenously or intrarectally. Viral titers in the first group ofanimals ranged from 10⁶ to 10⁸ before dosing began. All animalsdemonstrated an initial rise in plasma viral SHIV RNA. After a period of2 to 3 weeks, titers began to decline and 3 of the 4 animals showed aresponse to therapy with average viral titers of 0.76 log below baselineat weeks 4 to 5 after initiation of treatment. By week 8, titers in allanimals had returned to baseline values. Blood glucose levels droppedsignificantly, alkaline phosphatase levels were elevated and SGOT/GGTvalues trended towards the high end of normal. No other significantchanges were observed in any of the parameters monitored. The CD4 levelsin all monkeys remained less than 100 cells/mm³ at the end of the firstprotocol.

[0865] Three of the five monkeys on the second regimen (Protocol 2)responded to the BrEA therapy with a greater depth and duration ofresponse than observed at the lower dose levels. In the respondinganimals, the average decline below baseline was 1.47 log. Thenon-responding animal from Protocol 1 responded when administered theBrEA formulation in Protocol 2. Two animals did not respond, one eachfrom the treatment experienced and treatment naive groups. The thirdregimen (Protocol 3) is ongoing and animals are being monitored.

[0866] The monkeys on this study were salvaged from an infectivity studyand the first cohort of four monkeys on study (Protocol 1) were expectedto live only a few weeks past the initiation of these experiments asthey were beginning to deteriorate due to disease related causes. Oneanimal died at day 356 from a toxic reaction to the anesthetic usedduring acquisition of a blood sample for analysis. At the time of thisapplication, the remaining monkeys are receiving multiple rounds oftherapy appear to be in good clinical health. Their survival was greaterthan 380 days from the time of infection. Treatment by intermittentdosing of the BrEA formulation was used. Three control monkeys wereinfected with 1-10,000 SHIV₂₂₉ TCID₅₀ units and did not receivetreatment. These animals are considered the no treatment arm of asurvival study. The mean time to death for pig-tailed macaques infectedwith SHIV₂₂₉ was 193 days. Monkeys receiving therapy remained in goodclinical health for over 350 days with CD4 levels less than 20 cells/mm³and without opportunistic infections or disease-related symptoms, otherthan a mild anemia in one animal.

[0867] These results show completely unexpected therapeutic responses bythe primates infected with the SHIV retrovirus, which is quite virulent.The results show that the majority of subjects in these treatmentprotocols not only had significantly prolonged survival compared tountreated controls, but also the clinical symptoms associated withretroviral infection improved dramatically, despite the fact that CD4counts remained low, i.e., less than about 100 CD4 cells/mm³ initiallyand less than about 20 CD4 cells/mm³ later in the treatment protocols.To date, results such as this, i.e., (1) good clinical health in amajority of subjects having low CD4 levels (less than about 150cells/mm³, especially less than about 75 cells/mm³) and (2) no clinicalsign of viral resistance to treatment despite intermittent dosing over aprolonged time period, are unprecedented in primates, humans or anyother animal. The SHIV₂₂₉ model is extremely pathogenic in pig-tailedmacaques. Events that occur in this model over several weeks wouldtypically take several years in humans infected with HIV. Treatment ofmonkeys infected with this virus and treated with commonly usedantiretrovirals, e.g., AZT, 3TC or a protease inhibitor, are notexpected to significantly affect the course of disease progression. Theclinical condition of the animals continues to improve, e.g., weightgain is about 8-15% per animal. These results show that the treatmentusing the intermittent dosing protocol is highly effective despite theapparent impairment of the subject's specific immunity, as shown by thelow CD4 counts. Increased CD4 counts may be attained using immunestimulators such as IL2 or they may increase spontaneously in somesubjects such as humans, depending on the treatment protocol, theduration of dosing or the subject's initial medical condition. Theantiviral effects shown here appear to function at least in part byenhancing the subject's immune responses, e.g., enhanced immune responseby phagocytic cells (NK cells, monocytes and/or macrophages), and/orenhancing any residual specific immune responses, if any, that thesubject may be able to muster.

Example 4 Human Treatment Protocol

[0868] A dose escalation clinical trial is performed using a nonaqueousformulation containing BrEA or another formula 1 compound(s) that isprepared essentially as described in example 1. The patients aretreatment naive or treatment experienced and about 3-10 patients areexamined at each dose level. The initial dose is 25 mg of BrEA oranother formula 1 compound(s) that is administered parenterally, e.g.,s.c. or i.m. The dose is administered once or once or twice per day for1-12 days, followed by no dosing for at least 7 days (e.g., 7 to 90days). Subsequent doses are administered once or once per day for 1-12days, followed by no dosing for at least 7 days (e.g., 7 to 90 days).Other dose levels tested are 20 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200mg, 250 mg and 300 mg with each dose administered once per day as asingle dose or as two, three or more subdivided doses. An efficacydosing trial is performed using the same dosing protocol as the doseescalation trial or it may alternatively comprise dosing once or twiceevery other day for 3-17 days, followed by no dosing for 7-90 days andthen repeating the dosing once or twice every other day for 3-17 days.This protocol is repeated indefinitely (e.g., at least about 3-18months) using the optimal dose(s) obtained from the dose escalationtrial, e.g., about 10-200 mg/day of a formula 1 compound.

Example 5 Animal Pharmacological Studies

[0869] Nonclinical studies were conducted using an oral and asubcutaneous formulation of BrEA. Rats were orally administered ¹⁴C BrEAsolubilized in different excipients to determine the levels of drug inblood and various tissues. The results of these preliminarypharmacokinetics studies indicated that the absorption of BrEA by oraladministration is about 0.1 to 15%, with at least about 80% excreted inthe feces.

[0870] The nonaqueous BrEA formulation of example 1 was administered asa single subcutaneous dose to rabbits. More than 90% of the drug leftthe injection site within 24 hours of administration, and reached amaximum concentration in the plasma of about 1.2 % of the injected doseat eight to twelve hours post administration. The circulating half-lifeof the drug in the plasma was about twelve hours. The drug did notaccumulate to a significant extent in any major organ and was primarilyexcreted in the urine.

[0871] BrEA was administered subcutaneously to rats using theformulation of example 1. Approximately 90% of the drug left theinjection site within 24 hours of administration, and reached a maximumconcentration in the plasma of about 0.2% of the injected dose at onehour post administration. Elimination from the plasma was biphasic, withhalf-lives of about 12 and 72 hours respectively. BrEA did notaccumulate to a significant extent in any major organ, and was excretedprimarily in the feces. A study is also performed in Rhesus Monkeys withthe example 1 formulation to determine plasma pharmacokinetics.

[0872] A pharmacokinetic analysis of ¹⁴C BrEA in plasma was conducted intwo female Rhesus Monkeys. Trace labeled compound(16α-bromo-3-beta-hydroxy-5α-[4-¹⁴C]-androstan-17-one [50 mCi/mmole])was used at a dose of 1 mg/kg as a subcutaneous injection in thescapular region using an injection volume of 1 mL/kg. The BrEA wasformulated in 25% polyethylene glycol 300, 12.5% absolute ethanol, 5%benzyl benzoate, and qs with propylene glycol. 40 μCi were injected peranimal. Blood samples were taken at 0, 0.5, 1, 2, 4, 8, and 24 hours fordetermination of ¹⁴C activity. The radioactivity in the plasma rose tonear peak concentration in 8 hours and remained at approximately thesame level through the end of the study at 24 hours.

[0873] A pharmacokinetic analysis of ¹⁴C BrEA was conducted in NewZealand White rabbits. Twenty μCi of ¹⁴C16α-bromo-3-beta-hydroxy-5α-[4-¹⁴C]-androstan-17-one (50 mCi/mmole) plus1 mg/kg unlabeled BrEA was administered to each of three New ZealandWhite rabbits as a subcutaneous injection in the scapular region usingan injection volume of 1 mL/kg. The drug was formulated in 25%polyethylene glycol 300, 12.5% absolute ethanol, 5% benzyl benzoate, andqs with propylene glycol. Blood samples were taken at 0.5, 1, 2, 4, 8,12, 24 hours for all three animals, and at 48 hours for two of theanimals. Twenty-four and 48 hours after administration, one and twoanimals respectively, were sacrificed, and the following organs/tissueswere collected: brain, heart, kidneys, liver, lungs, skeletal muscle,spleen, and injection site muscle and skin. In addition to the organsand tissues, urine and feces were collected as well as the cage wash.BrEA did not accumulate to a significant degree in any of the organslisted above. Of the organs, the greatest mass of drug was observed inthe liver, containing approximately 0.8% and 0.12% of the injected doseat 24 and 48 hours, respectively (average 0.13%). Percentage of Drug inOrgans (Rabbits) Animal 201 Animal 301 Animal 302 Organ or Tissue 24hours 48 hours 48 hours Brain 0.005 0.002 0 Heart 0.008 0.003 0.002Kidneys 0.155 0.055 0.050 Liver 0.76 0.145 0.125 Lungs 0.029 0.019 0.011Spleen 0.002 0 0 Skeletal muscle 0.002 0 0 (sample wt. in grams) (3.8 g)(6 g) (5 g) Skin 0.008 0.002 0.004 (sample wt. in grams) (8 g)   (6 g)(9 g)

[0874] The average percentages of the administered dose in whole bloodwas calculated by multiplying the concentration of drug in whole bloodby the assumed volume of blood in the animals, 200 mL. The amount ofdrug in the blood reaches a maximum at around 8 hours, and a smallamount was still evident at 48 hours. The amount of BrEA in whole bloodwas consistently lower than in plasma, suggesting the drug is not takenup to an appreciable extent by red blood cells.

[0875] In vivo experiments were conducted to determine thebioavailability of BrEA via oral administration using differentformulations. BrEA was (1) solubilized in soya oil, vitamin E oil, amixture of vitamin E and cremophore or (2) BrEA was micronized andcombined with or without a surfactant. These formulations are describedbelow. The formulations were administered orally to rats and BrEA levelswere determined in the blood, liver, spleen, kidney, and the lymphnodes. In the studies using micronized BrEA, the brain was evaluated fordrug uptake. Twenty-four hour urine and feces were collected when BrEAwas solubilized in vitamin E and soya oils and vitamin E mixed withCremophore. The data from these studies indicate that BrEA enters intothe lymphatics but is eliminated rapidly from the other tissues. Theamount of ¹⁴C radioactivity recovered in the feces 24 hours afteradministration was 78 to 83%. A brief summary of each experiment isprovided below and the results are provided in Table 6.

[0876] BrEA (5 mg in 1.0 mL of soya oil or vitamin E oil) supplementedwith ¹⁴C-labelled BrEA was administered intragastrically to rats.Solubilization of BrEA in the vitamin E or soya oil was facilitated with50 μL ethanol. Animals (3/time point) were assayed at 1.5, 3, 5.5, and24 hours after administration and the ¹⁴C-radioactivity was measured inthe blood, liver, spleen, kidney, lymph nodes and 24-hour feces andurine. The results indicate that, on the basis of ¹⁴C-radioactivity,some of the BrEA is taken into the lymphatic system. The uptake isgreater with soya oil than vitamin E oil in the blood, liver, and lymphnodes.

[0877] BrEA (5 mg in 1.0 mL of a vitamin E and cremophore) supplementedwith ¹⁴C-labelled BrEA was administered intragastrically to rats.Solubilization of BrEA in the vitamin E-cremophore mixture wasfacilitated by the adding 60 μL ethanol. Animals (4/time point) weresacrificed at 2, 3, 5.5, and 24 hours and ¹⁴C-radioactivity was measuredin the blood, liver, spleen, kidney, lymph nodes and 24 hour feces andurine. The results indicate that a small portion of the drug is taken upby the lymphatic system. Judging from the values in plasma, liver andlymph nodes, it appears that drug uptake is slower compared with soy oilor vitamin E and its presence in the tissues is more persistent.

[0878] Rats, in groups of three males, were orally administered 1.0 mLof 0.9% NaCl containing 10 or 32 mg BrEA micronized with a surfactant,Synperonic PE/F 127 (2.5% wt/wt). Rats were examined at 1.5, 5 and 24hours after administration. Blood, liver, spleen, kidney, lymph nodes,and brain were assayed for ¹⁴C radioactivity. The levels of BrEA in theblood, in comparison to the experiments with BrEA in Vitamin E oil andsoya, were higher, 0.3% at 1.5 hours, and increased after 5 hours to0.8% and 0.9% of the 10 and 32 mg dose, respectively. Additionally, thevalues in the lymph nodes were similar to those measured at 1.5 hoursand the levels were sustained at 5 hours (5.3 and 5.0%) and 24 hours(3.7 and 3.1%) for the 10 and 32 mg dose, respectively (refer to Table6).

[0879] In a repeated dose experiment, rats were intragastricallyadministered 1.0 mL 0.9% NaCl containing 2 mg BrEA micronized withSynperonic PE/F 127 (2.5% wt/wt) every 6 to 16 hours. Rats (3/timepoint) were sacrificed at 40, 72, 84, 90 and 96 hours after the firstadministration. Blood, liver, spleen, kidney and lymph nodes wereassayed for ¹⁴C radioactivity. Higher levels in the blood, liver,kidneys and lymph nodes were noted in this experiment over previousstudies.

[0880] Rats, in groups of three males, were orally administered 1.0 mLof 0.9% NaCl containing 2, 4 or 10 mg BrEA micronized without asurfactant. Rats were sacrificed at 1.5, 5 and 24 hours afteradministration and blood, liver, spleen, kidney, lymph nodes and brainwere assayed for ¹⁴C radioactivity. The concentration of BrEA micronizedwithout a surfactant in the observed tissues was lower than BrEA plus asurfactant.

Example 6 Inhibition of Parasites in vitro

[0881] For in vitro antimalarial testing, micro-titer plates were used.The concentration of drugs was prepared as pMol/well according to WHOstandard procedures (WHO, 1990). The test compound was dissolved in 15%DMSO in sterile RPMI-1640. Both chloroquine sensitive (e.g., WS/97) andresistant (e.g., MN/97) isolates of Plasmodium species are used.

[0882] A schizont inhibition assay was performed as follows. Themicro-titer plates were predosed with various concentrations of the testcompound. 50 μL of parasitised erythrocyte suspension in RPMI-1640 (0.2mL erythrocyte+0.3 mL serum+4-5 ml RPMI-1640) were dispensed inmicrotiter wells that contained various concentrations of drug.Triplicate readings were made for each concentration.

[0883] A ³H-hypoxanthine incorporation assay was performed as follows.The testing was carried out according to the procedure of Desjardins etal. 1979. After 30 hr culture at 37 degrees C., the same microtiterplates from schizont inhibition assays with another triplicate wellswere pulsed with ³H-hypoxanthine for overnight. The cell suspensionswere washed twice on millipore glass fiber filter with Millipore filterapparatus. The filter discs were counted for DPM by a Beckman LS6000β-scintillation counter. The activity of the drug was measured byplotting DPM against concentration of drug. Activity of compoundsagainst Chloroquine sensitive T996/86 P. falciparum in vitro EtianicAcid Concentration Etienic Acid Methyl (μM) DHEA* BrEA* Methyl Ester*Ester* 30 65.6 98 60 61.5 15 44 60.1 45.7 47.4 7.5 38.3 50 40.9 45.33.25 37.2 43.7 46 41.4 1.875 23.2 40.9 41 43.4 0.938 37.2 31.8 43.3 47.1IC₅₀ 19.0 μM 7.5 μM 19.5 μM 17.5 μM Concentration (nM) % InhibitionChloroquine Chloroquine 200 95.9 100 94.6 50 97.3 25 94.5 12.5 86.8 6.2527.2 IC₅₀ 9.0 nM

[0884] The activity of 16α-chloroepiandrosterone and16α-bromodehydro-epiandrosterone against chloroquine sensitive T996.86and chloroquine resistant KI P. falciparum in vitro is shown below.T996.86 KI 16-chloroepiandrosterone IC₅₀ −9.25 pg/mL ˜9.25 μg/mL DHEA-BrIC₅₀ −25.0 pg/mL ˜25.0 μg/mL

[0885] Other formula 1 compounds, e.g., any compound in compound group 1through 25-6 are used in a similar manner to inhibit Plasmodiumparasites.

Example 7 Four-Day in vivo Protocol for Inhibition of Plasmodium berghei

[0886] The 4-day suppressive test has been widely used and it can beperformed within a 1-week period. The test consists of the inoculationof parasitised erythrocytes on the first day of the experiment (D₀),followed by an injection of the test compound, which is alsoadministered on the 2^(nd), 3^(rd) and 4^(th) days of the protocol. Onthe 5^(th) day, blood films are taken and antimalarial activity isassessed either by calculating parasitemia, or by scoring parasitenumbers on a predetermined scale (i.e., 1-5). Peters (Ann. Trop. Med.Parasitol. 64: 25-40, 1970) described a basic procedure using this 4-daytest.

[0887] The protocol is summarized as follows. Five female TO mice wereused per test group. P. berghei HP15 ANKA parasites were collected bycardiac puncture using a heparinised syringe from a donor mouse having a30+% parasitaemia. The blood was diluted with diluting agent (50%HIFCS+50% sterile PBS) to a final concentration of 1% parasitaemia or1×10 ⁷ infected erythrocytes per 0.2 mL of the infecting suspension.Each mouse was inoculated intravenously, which produced a more uniforminfection rate than intraperitoneal administration of 0.2 mL of theinfecting suspension. Test compounds were prepared at doses of 100 mg/kgin (16.7% DMSO+83.3% Celacol). The steroid formulations wereadministered intraperitoneally 2 hours after parasite inoculation. Thecompounds were administered once a day starting on D₀, and continued onthe following three days. Blood films were made from tail blood on theday after the last dosing of compound and the blood was fixed with 100%methanol and stained with 10% Giemsa. Parasitaemias were scored on ascale of 0-5, where 5 is equal to the control.

[0888] An inoculum of 1% parasitaemia 1×10⁷ erythrocytes/mL, 0.2 mL permouse (female strain TO mice), was delivered by intravenous injection.Drug administration commenced 2 hours after inoculation on Day 1 andcontinued for 3 days. The results are shown below from blood films fromall 20 mice on Day 5 when parasitaemias were assessed. ParasitaemiaCompound Treatment Score (0-5) BrEA 100 mg/kg × 4 days i.p.* 1 EtienicAcid 100 mg/kg × 4 days i.p. 2 DHEA 100 mg/kg × 4 days i.p. 1Chloroquine  3 mg/kg × 4 days i.p. 1 control N/A 5

[0889] In a similar protocol, mice are inoculated with a solutioncontaining 1×10⁷ erythrocytes/mL by I.V. injection. Two hours later givedrug is delivered by I.V. injection. BrEA or another formula 1 compoundis given (0.2 mL I.V. or S.C.) once a day for 4 days. Tail snips areused to obtain blood after the study. Mice infected with P. berghei wereused to obtain infected cells. Parasites are harvested from cardiacmouse blood, and uninfected mice are infected using 0.2 ml of blood with14% parasitaemia per mouse I.V. Two hours later, the first dose of BrEA(100 mg/kg I.V. or S.C.) is delivered to the infected animals. The BrEAformulation was a sterile solution containing 15 mg/mL of BrEA in 45%hydroxypropyl-β-cyclodextrin and 0.9% saline. At 1, 2, 3 and 4 daysafter the infection of the animals, BrEA (100 mg/kg I.V. or S.C.) isdelivered to the infected animals. No deaths occurred in the groupreceiving I.V. BrEA at day 30, but all control animals were dead by day10. All animals treated with BrEA by S.C. delivery were dead by Day 11.

Example 8 Rat in vitro and in vivo Study

[0890] In the in vitro protocol the parasite (Plasmodium falciparum,chloroquine sensitive strain WT and chloroquine resistant strain Dd2)level is adjusted to 1 % and the hemocrit is adjusted to 7% with medium.Using a 96 well plate, 50 μL of parasite and 100 μL of drug mixed withmedia are added to each well and the procedure is done in triplicate.The plate is placed in a chamber containing a physiological gas mixtureand incubated at 37° C. The media/drug mixture is changed at 24, 48 and72 hours. On day 5 (96 hours) slides of each well are made, stained withGemsia and 500 red blood cells are counted for each slide. Thetriplicates are averaged and data are reported in percent inhibition.

[0891] In the in vivo protocol, Lewis rats weighing 80-85 grams weregiven a standardized IP injection of parasite (Plasmodium berghei). Ratswere then intravenously injected 2 hours later with one of thetreatments described in the table below, returned to their housing, fedstandard lab chow and allowed free access to water. Animals were weighedand treated again 24, 48, and 72 hours after the first treatment andagain returned to their housing and they were allowed free access tofood and water. The animals were weighed again and then bled using a26-gauge needle on day 5, 11 and 28 post inoculation. Hemocrits weremeasured and blood smears are prepared for each rat. The blood smearswere then stained using Gemsia and the level of parasitemia (defined asthe percent of red cells with parasites) was determined. Animals wereagain returned to their housing and observed twice daily for evidence ofprogressive disease, defined as listlessness and or adverse drugreaction, which is defined as a loss of 20% of original body weight, fora total of 28 days. If either progressive disease or drug reaction isnoted, the animals are euthanized.

[0892] The BrEA formulation was a sterile solution containing 15 mg/mLof BrEA in 45% hydroxypropyl-β-cyclodextrin and 0.9% saline. Group 1Group 2 Group 3 Group 4 Control 0.9% Chloroquine BrEA Low BrEA Highsaline Control Dose Dose 40 mg/kg 30 mg/kg 60 mg/kg

[0893] The intravenous injections were given on days 0, 1, 2 and 3 andthe results are shown below. The results showed that treatment in vivowith a formulation comprising BrEA reduced parasitemia to a levelcomparable to that seen with the chloroquine (“Clq”) control. Theresults are summarized below. % RBC parasitemia Day 4 saline control 16%chloroquine control 10% low dose BrEA  9% high dose BrEA  7% Day 11saline control 36% chloroquine control 16% low dose BrEA 12% high doseBrEA 11%

Example 9 Human Clinical Study—Parasite Infection

[0894] Response to drug treatment was graded as per World HealthOrganization criteria (WHO 1973) in infected patients. Evaluation oftherapeutic response was determined using the parasitic and feverclearance times. Parasite clearance was expressed as three indices; thetime for the parasite count to fall by 50% of the pre-treatment(baseline) value (PC₅₀), (ii) the time for the parasite count to fall by90 % of the baseline value (PC₉₀) and (iii) the time for the parasitecount to fall below the level of microscopic detection (parasiteclearance time PCT) (N. J. White and S. Krishna Trans. R. Soc. Trop.Med. Hyg. 83: 767-777, 1989; White et al., J. Infect. Dis. 165: 599-600,1992; White et al., J. Infect. Dis. 166: 1195-1196, 1992). The feverclearance time was defined as the time from drug administration till theoral or rectal temperature fell to or below 37.2° C. and remained so forat least 48 h.

[0895] Venous blood (5 mL) was obtained from two patients beforetreatment and at 4, 6, 8, 12, 18, 20, 24, 30 and 36 h after treatment orat 4 or 6-hourly intervals after treatment until there was completeclearance of peripheral parasitemia. Blood was collected aseptically andtransferred to 10 mL syringes containing 2 mL of acid citrate dextrose(ACD) for in vitro culture. Prior to incubation, the plasma wasseparated from the red blood cells and the red blood cells were washedtwice. Parasites were cultured by modification of standard in vitroculture techniques (W. Trager and J. B. Jensen, Science 193:673-675,1976; A. M. Oduola et al., J. Protozool. 39: 605-608, 1992). Sampleswere dispensed into sterile centrifuge cubes within 10 min of collectionand spun down. The supernatant plasma was stored while the packed cellswere washed twice with culture medium (washing medium, RPMI-1640 medium,containing 25 mM HEPES buffer and 25 mmol/L NaOH). The buffy coat wasremoved by vacuum aspiration. A 1:10 fold dilution was done for eachblood sample with complete washing medium [CMP (washing mediumsupplemented with 10% human plasma)]. One milliliter each of the samplewas transferred into 2 wells of a 24 well micro culture plate. Cultureswere incubated at 37 degrees C. in an atmosphere of 5% CO₂, 5% O₂ and90% N₂ premixed gas. The culture medium was changed daily and thin bloodsmears were prepared for microscopy at 24 and 48 h after the culture hasbeen set up. The culture samples were diluted with unparasitized washedtype A Rh-positive red blood cells if the proportion of parasitized redblood cells was more than 2%.

[0896] Microscopy.

[0897] During the in vivo study, thin and thick blood films were fixedwith dehydrated methanol (100%) and heat, respectively, were stainedwith 10% Giemsa for 20 min. Parasitemia was quantified in thin films bycounting 2000 red blood cells in clear contiguous fields and finding theproportion that was parasitized. In thick films, parasitemia wasquantified by counting parasites against leukocytes. A film was declarednegative if no parasites were found after examination of 200 microscopefields of a thick smear. During in vitro and ex vivo study, pretreatmentthin and thick smears were, graded for ring stages by the method ofJiang as modified by Li et al. (J. B. Jiang et al, Lancet 2(8293):285-288, 1982; K. Silamut and N. J. White Trans. R. Soc. Trop.Med. Hyg.87: 436-443, 1993; X. L. Li et al, Chi. J. Parasitol. Dis. 12: 296,1994). Approximately 5000 erythrocytes were counted in clear contiguousfields 24 and 48 h after incubation of blood obtained at each time pointand graded for maturity into tiny rings, small rings, large rings,pigmented trophozoites and schizonts. Functional viability was estimatedas the percentage of asexual ring forms capable of maturing to pigmentedtrophozoites or schizonts after 24-48 h of in vitro culture (W. M.Watkins et al., Trans. R. Soc. Trop. Med. Hyg. 87: 75-78, 1993).

[0898] Calculation of Parameters.

[0899] The patients presented with acute symptomatic severe non-cerebralpure P. falciparum malaria. They had oral fluid intolerance, bodytemperatures greater than 39° C., greater than 5000 parasites per microliter of blood, asexual parasitemia and they had a negative urine testfor antimalarial drugs. They were administered 25 mL intravenously everyfour hours with BrEA suspended in sterile 45% β-cyclodextrin in salineat a concentration of 25 mg/mL. This regimen was continued for fourdays. Parasitemia quantification and clinical examination were done onceevery 6 hours for the first 72 hours, followed by daily assessment ofthe parameters up to day 7 (168 hrs) and thereafter on day 14.

[0900] Blood films were Giemsa-stained and parasitemia quantificationwas done in thick films by counting 2000 parasites against leukocytes,and the thin films by finding the proportion of infected red bloodcells. Response to drug treatment was graded according to WHO criteria.Evaluation of therapeutic response was done using the parasitic andfever clearance times. Parasite clearance was expressed as threeindices: The time for the parasite count to fall by 50% of thepre-treatment (baseline) value (PC₆₀); to fall by 90% of the baselinevalue (PC₉₀); and to fall below the level of microscopic detection(parasite clearance time) PCT.

[0901] The fever clearance time was defined as the time from drugadministration until the oral/rectal temperature fell to below 37.2degrees C. and remained so for greater than 48 hours. The parasiteclearance rate at day 14 was 100%. The clinical response thus includedan effect on parasitemia in both patients and amelioration of one ormore symptoms of infection. Intravenous BrEA Malaria Patient TrialPatient A Patient B Fever clearance time 12 hrs 18 hrs Parasiteclearance times Time to 50% clearance 18 hrs 24 hrs Time to 90%clearance 24 hrs 48 hrs Time to 100% clearance 48 hrs 64 hrs

Example 10 Cellular Studies in vitro

[0902] The effect of BrEA on pentosephosphate shunt (PPS) activity innormal human RBC was examined using whole cells. Sinceglucose-6-phosphate dehydrogenase (“G6PD”) is the limiting enzyme of thePPS, PPS flux measurement is considered to better reflect G6PD activityin the whole cell compared to G6PD activity measurement in a celllysate. G6PD activity measured in a cell lysate is typically about1100-fold higher than the PPS flux in whole resting unstimulated RBC(G6PD activity in cell lysate: 165; PPS flux 0.142 micromoles/hour/mlRBC). PPS flux and G6PD activity in the whole RBC depends on a number offactors (the concentration of NADPH, NAD, and ATP, and intracellularpH), which are kept constant if the measurement is performed in thelysate and may vary in the whole RBC. Levels of G6PD activity in cellsis considerably above normal basal needs and inhibition of overall G6PDactivity might have no or minor consequence on PPS flux in the wholecell. For example, RBC with the Mediterranean G6PD mutant with about 1-3percent residual activity compared with normal individuals have noimpairment in basal PPS flux, but show impaired flux when flux throughPPS is stimulated by methylene blue addition. A series of experimentswere perfromed using varying amounts of BrEA and PPS flux was measuredin unstimulated basal RBC and in methylene-blue (MB)-stimulated RBC.

[0903] The data below shows PPS flux (micromoles/hour/ml RBC) in basalunstimulated, and MB-stimulated normal RBC. Different concentrations ofBrEA (0.3, 3.5 and 7 micromolar, final) were supplemented to suspensionsof washed RBC suspended in RPMI, pH 7.4 at 10% hematocrit, whereby PPSflux was immediately measured without further incubation and withoutfurther washings. A minor inhibition of MB-stimulated PPS flux wasobserved with BrEA at 7 μM. PPS flux control, unstimulated RBC 230 DMSOcontrol, unstimulated RBC 270 DMSO control, MB stimulated RBC 5090 0.3μM BrEA, unstimulated 250 0.3 μM BrEA, MB stimulated 5000 3.5 μM BrEA,unstimulated 270 3.5 μM BrEA, MB stimulated 4950 7 μM BrEA, unstimulated295 7 μM BrEA, MB stimulated 4660

[0904] The data below shows average values of 3 experiments, wherebasal, unstimulated, and MB-stimulated PPS flux (micromoles/hour/ml RBC)was measured in normal RBC. In these experiments, differentconcentrations of BrEA ˜0.8, 8 and 80 micromolar, final) weresupplemented to suspensions of washed RBC suspended in RPMI, pH 7.4 at10% hematocrit. After a 90-min incubation at 37° C. with and withoutBrEA, PPS flux was measured. The results showed a dose-dependentinhibition of MB-stimulated PPS flux. Inhibition was 10% at 8 micromolar(p=0.006 vs control+DMSO) and 25% at 80 micromolar (p=0.002 vscontrol+DMSO). PPS flux control, unstimulated RBC 430 control, MBstimulated RBC 5410 DMSO control, unstimulated RBC 480 DMSO control, MBstimulated RBC 4890 0.8 μM BrEA, unstimulated 410 0.8 μM BrEA, MBstimulated 4930 8 μM BrEA, unstimulated 450 8 μM BrEA, MB stimulated4430 80 μM BrEA, unstimulated 450 80 μM BrEA, MB stimulated 3660

Example 11 Inhibition of Parasite Growth

[0905] The effect of Epi (16α-bromo-epiandrosterone) on parasite(Plasmodium falciparum) growth was shown. EPI was active at aconcentration of 1 μM. Parasitemia after treatment Time 0 24 hrs 48 hrs72 hrs control + DMSO 5% 5.40% 3.10% 5.20% Epi 1 μM 5% 5.70% 5.50% 1.60%Epi 10 μM 5% 5.60% 0.90% 0 Epi 100 μM 5% 0 0 0 Epi 500 μM 5% 0 0 0control + DMSO 2% 8.80%   11%   8% Epi 50 nM 2% 9.90% 9.20% 8.30% Epi 1μM 2% 5.80% 6.10% 2.10% Epi 2.5 μM 2% 7.30% 5.80% 3.20% Epi 5 μM 2%5.40%   6% 1.80% Epi 10 μM 2% 4.20%   3% 0 Epi 50 μM 2% 0 0 0

[0906] Parasitemias were determined by standard methods (microscopicinspection of at least 500 cells, stained with Diff-Quick™ (Baxter).Parasites were cultured under standard conditions in RPMI-1640supplemented with Hepes/Glucose (10 mM), glutamine (0.3 g/liter) and 10%human plasma. The hematocrit was 1%.

Example 12 Stimulation of Phagocytosis

[0907] The capacity of BrEA to influence phagocytosis of Plasmodiumparasite-infected RBC is examined using adherent human monocytes. Theparasitemia level is about 8-10% and human monocytes are obtained frombuffy coats from blood as follows. Peripheral blood mononuclear cellsare separated from freshly collected platelet-poor buffy coats discardedfrom blood samples of healthy adult donors of both sexes. Separatedcells are washed once with luke-warm PBS supplemented with 10 mM glucose(PBS-G) and resuspended at 5×10⁶ cells/mL in ice-cold RPMI 1640 mediumsupplemented with 23 mM NaHCO₃ and 25 mM Hepes, pH 7.4 (RMBH). DynabeadsM450 Pan B and Pan T (Dynal) are added to cells in a 4:1 ratio for 20min at 4° C. B-lymphocytes and T-lymphocytes are removed as specified bythe manufacturer. The remaining monocytes are washed 2 times in RMBH,resuspended in AIM V cell culture medium (Gibco) at 1×10⁶ cell/mL. Themonocyte layer is collected, washed with PBS-G at 37° C. and resuspendedin AIM V medium at 1×10⁶ cells/mL. Purified cells are >90% monocytes asassessed by CD14 expression.

[0908] Phagocytosis of opsonized parasitized RBC (PE) is determined asfollows. Phagocytosis of fresh-serum opsonized PE is initiated by mixing10 PE/monocyte. Suspensions are briefly centrifuged (150×g for 5 sec atroom temperature) to improve contact between PE and monocytes. To avoidattachement of monocytes after centrifugation and during the wholeincubation period, cells are kept in suspension at 5×10⁶ cells/5 mL AIMV medium in 6 cm diameter teflon bottom dishes (Heraeus) in a humidifiedincubator (95% air, 5% CO₂) at 37° C. On average, at least 90% of themonocytes phagocytose PE, as assessed by microscopic inspection. Controlcells are kept under similar conditions without phagocytosis.Quantitative assessment of phagocytosis is performed by a previouslydescribed bioluminescence method (E. Schwarzer, et al., Br. J. Haematol.1994 88: 740-745).

[0909] Erythrocyte treatments and parasite cultures are as follows.Fresh blood (Rh+) is used to isolate erythrocytes (RBC). Washed RBC areinfected with schizont/trophozoite parasite stages (Palo Alto strain,mycoplasma-free). Stage specific parasites are isolated by thePercoll-mannitol method. Briefly, normal schizont-stage parasitized RBC(SPE) separated on Percoll-mannitol gradient (parasitemia>95% SPE) aremixed with RBC suspended in growth medium (RPMI 1640 medium containing25 mmol/L Hepes, 20 mmol/L glucose, 2 mmol/L glutamine, 24 mmol/LNaHCO₃, 32 mg/L gentamicin and 10% AB or A human serum, pH 7.30) tostart synchronous cultures at selected hematocrit values. The inoculumparasitemia is adjusted to 20% normal SPE for isolation of ringparasitized RBC (RPE) and to 5% normal SPE for isolation oftrophozoite-stage parasitized RBC (TPE). At 14-18 hours after inoculumparasites are at ring-stage in the first cycle; at 34-33 hours,parasites are at trophozoite-stage in the first cycle; and at 40-44hours after inoculum parasites are at schizont-stage in the first cycle.RPE, TPE and SPE are separated on Percoll-mannitol gradients. Theparasitemia is usually 8-10% RPE, and >95% TPE. Nonparasitized andparasitized RBC are counted electronically. To assess total parasitemiaand relative contribution of RPE, TPE and SPE, slides are prepared fromcultures at indicated times, stained with Diff-Quik™ parasite stain andabout 400-1000 cells are examined microscopically.

[0910] The effect of a formula 1 compound such as BrEA in parasitizedRBC is examined using various concentrations of the compound, e.g.,BrEA, e.g., 0.5 μM, 1 μM, 10 μM, 25 μM and 50 μM.Trophozoite-parasitized RBC, schizont-parasitized RBC orring-parasitized RBC are examined as described.

Example 13 Human Malaria Clinical Trial

[0911] The clinical trial protocol that incorporates about 15-20patients is established. For a phase I, II/II or II trial, the patientsare mildly infected with one or more Plasmodium parasites and they aremildly symptomatic (less than about 8-10% parasitemia of RBC). Beforetreatment, the patients are optionally tested for infection with HIV,HCV, TB, and Cryptosporidium. Patients with one or more co-infectionsare given standard care for the coinfection. The patients arehospitalized for treatment for one week. Two or more dose groups, e.g.,25, 50 or 100 mg/day of BrEA administered parenterally, e.g., byintramuscular, subcutaneous or intravenous injection, on 3,4 or 5 daysof the week when patients are dosed. Dosing is on consecutive days or onan intermittent schedule, e.g., 2, 3 or 4 doses with one doseadministrered every other day.

[0912] The formulation containing BrEA is as described herein, e.g., theformulation of example 1 or a formulation that comprises 100 mg/mL BrEA,PEG300 ˜30% v/v, propylene glycol 30% v/v, benzyl benzoate 30% v/v andbenzyl alcohol 2% v/v. At day 5-7, if less than about 50% reduction inparasitemia is observed, the patients are given standard care formalaria (mefloquine). During the week of treatment and for 1, 2 3, ormore weeks there after, blood samples are taken periodically forevaluation of parasitemia, pharmacokinetics, plasma cytokines (e.g.,IL-2, IL-4, IL-10, IGF1, γIFN, GM-CSF), and intracellular cytokines(e.g., IL-2, IL-4, IL-10, IGF1, γIFN, GM-CSF). The patients areoptionally treated again at about 2 to 12 weeks after the initialdosing, using the same or a similar protocol as that used in the initialdosing protocol.

[0913] An exemplary open-label study of a BrEA formulation administeredintramuscularly to semi-immune patients with uncomplicated malaria isconducted. The formulation comprises 100 mg/mL BrEA, PEG300 ˜30% v/v,propylene glycol 30% v/v, benzyl benzoate 30% v/v and benzyl alcohol 2%.Patients will remain at the hospital as in-patients for the first 7 daysof the study. Patients will receive one daily intramuscularadministration of 50 mg or 100 mg of BrEA for 5 consecutive days. Dailyevaluation for the first 7 days, and up to study day 14, may includeparasitemia evaluation (twice daily), chemistry, hematology and druglevels (pharmacokinetic evaluation). If, after study day 7, theparasitemia levels decrease from the screening value and the patient isclinically stable, the patient may be followed on a daily basis forparasitemia (twice daily) for up to an additional 7 days as hospitalin-patients. If a patient becomes clinically unstable at any time duringthe study, the patient will be discontinued and may be offered thestandard treatment for malaria. Patients deficient inglucose-6-phosphate dehydrogenase enzyme may be excluded, since BrEAinhibits the enzyme. Other considerations that may lead to exclusion ofpatients from the trial include patients diagnosed with any of thefollowing: severe anemia (hematocrit<21% or hemoglobin<7 g/dL); renal orliver failure by history and/or laboratory results respiratory distressas evidenced by dyspnea or respiratory rate≧30 per minute; hypotension(systolic blood pressure<90 mm Hg); tachycardia (heart rate>130beats/minute); pregnant or breast-feeding women; significant activeco-morbid illness (acute medical diagnosis requiring specific therapy;patients with parasitemia>10% on peripheral smear.

[0914] Blood samples may be collected from each patient for futureclinical evaluation such as the determination of activation markers orimmunological analyses (e.g., assay for intracellular or extracellularinterleukins IL-1β, IL-2, IL-4, IL-6, IL-10 and IL-12, γIFN and TNFα).

Example 14 Liposome Formulation

[0915] Liposomes suitable for parenteral administration are prepared asfollows. 400 mg of phosphatidyl choline and 80 mg of BrEA are dissolvedin chloroform and methanol (2:1 v/v) and the solution is dried by rotaryevaporation under reduced presure. The resulting film is rehydrated byadding 8.0 mL of a 0.9% w/v NaCl solution and agitating the solution.The sizes of the liposomes are optionally measured, e.g., by photoncorrelation spectroscopy (Malvern Zetasizer 3000 or equivalent). Theliposomes are optionally sized by, e.g., sonication to reduce theaverage size below 400 mn, or by filtration using suitable filters.Similar procedures are used to prepare liposome preparations thatcontain a formula 1 compound at about 15-100 mg/mL. The formulation isused to deliver the compound orally or parenterally (I.M., S.C., I.V.).

Example 15 Cyclodextrin Formulation

[0916] A cyclodextrin formulation containing BrEA is prepared asfollows. 45 g of hydroxypropyl-β-cyclodextrin is added to 1 L of sterilephysiological saline and the mixture is stirred for about 4-24 hours,until a clear solution is obtained. Non-micronized BrEA is added to givea concentration of 20 mg/mL and the mixture is stirred until a clearsolution is obtained. The solution is sterilized by filtration using a0.2 μm pore size filter and dispensed into sterile containers. Similarprocedures are used to prepare cyclodextrin formulations that contain aformula 1 compound at about 15-100 mg/mL. The formulation is used todeliver the compound orally, parenterally (I.M., S.C., I.V.) or by abuccal or sublingual route.

Example 16 Suppository Formulation

[0917] A suppository formulation containing a formula 1 compound such asBrEA is prepared as follows. Sufficient non-micronized BrEA is measuredto obtain a desired number of units that comprise 500 mg each of BrEA.The BrEA is blended with with a suppository base, e.g., triglyceridefrom edible vegetable oil, to provide desired characteristics, e.g., afree fatty acid content of about 0.1% w/w, a saponification value ofabout 242, an iodine value of about 3, moisture at about 0.1 % w/w and aclosed capillary melting point of about 35° C.

Example 17 Human HCV Clinical Trial

[0918] A female patient infected with HIV and HCV was dosed I.V. withBrEA for 3 consecutive days using a formulation that contained 20 mg/mLBrEA in 45% w/v hydroxypropyl-β-cyclodextrin and saline. Four mL of theformulation (80 mg BrEA) was administered to the patient every 4 hoursduring the 3-day treatment period. The patient's predosing HCV level was6.5 Log₁₀ as measured by PCR and the HCV level was 6.2 Log₁₀ on thefirst day of dosing, 5.5 Log₁₀ on the 3^(rd) day of dosing and 4.9 Log₁₀three days after the last dose was administered. HIV RNA levels asmeasured by PCR was 5.2 Log₁₀ (predosing), 5.8 Log₁₀ (first day), 5.9Log₁₀ (third day) and 5.4 Log₁₀ (day 6). The NK cell counts (cells/mm³)were 28, 41 and 38 at predosing, day 0 and day 3.

Example 18 Formulation

[0919] A formulation comprising 100 mg/mL BrEA, ˜30% v/v PEG300, 30% v/vpropylene glycol, 30% v/v benzyl benzoate and 2% v/v benzyl alcohol wasprepared by suspending BrEA in polyethylene glycol 300, and sequentiallyadding propylene glycol and benzyl benzoate, to form a solution, whichwas diluted to the final desired volume with additional propyleneglycol. The procedure is described below.

[0920] The calculated amount of polyethylene glycol 300 was added to acompounding vessel. Then, while mixing, the calculated amount of BrEAwas added to the vessel, and mixed for at least 5 minutes to form asmooth, creamy liquid propylene glycol was added to the vessel, andmixed for a minimum of 5 minutes to form a uniform suspension. Thecalculated amount of benzyl benzoate is added to the vessel, and mixedfor approximately 5 minutes to form a translucent liquid suspension.Propylene glycol was then added to achieve the desired finalformulation, and mixed for approximately 5 minutes. The drug solutionwas transferred to a volume dispensing device set to deliver 1.2 mL pervial. Under nitrogen pressure, the solution was filtered through two 0.2μm polyvinylidene fluoride filters in series into 2 cc amber glassvials. The vials were capped with Teflon-coated, butyl-rubber stoppersand crimp sealed.

Example 19 Opportunistic Infection Clinical Protocol

[0921] A double blind, randomized, placebo controlled study of 100 mg ofBrEA administered intramuscularly to late stage HIV-infected patients atrisk for opportunistic infections (OIs). HIV-1 seropositive patientswith a CD4 cell count≦100 cells/mm³, HIV RNA at 1×10⁶ copies/mL and aKarnofsky score of at least 60 are identified for potential inclusioninto the protocol. Patients in all clinical protocols must understandand sign a written informed consent form prior to screening evaluations.

[0922] BrEA in the formulation of example 16 is used. Administration ofdrug or vehicle will be for 3 to 5 consecutive days followed by about35-90 days of observation, e.g., 37 days of observation. An exemplarytreatment regimen comprises 5 days of treatment followed by 37 days ofobservation, which is repeated for a total of 7 courses over 42 weeks.The incidence rate of OIs as well as the time to resolution or controlof the OIs will be monitored and compared to a placebo control group.The patients may be monitored monthly for 2 or 3 months after completionof the study for follow-up. The incidence of OIs or conditionsassociated with AIDS are monitored, e.g., as tuberculosis (TB),candadiasis, Pneumocystis pneumonia (PCP), diarrhea, or Kaposi'ssarcoma, may be evaluated as protocol endpoints. If a patient isdiagnosed with one or more of the protocol specified opportunisticinfections, the protocol regimen a treatment for the OI will beinitiated, e.g., Fluconazole for Candidiasis or for PCP, trimethoprimand sulfamethoxazole or Dapsone. A similar protocol is used with otherformula 1 compounds.

Example 20 Human HIV Clinical Protocol

[0923] Patients infected with HIV are dosed with an i.m. injection of25-200 mg of BrEA using a formulation containing 100 mg/mL BrEA, PEG300˜30% v/v, propylene glycol 30% v/v, benzyl benzoate 30% v/v and benzylalcohol 2% v/v. The pateints are dosed once per day for 5 consecutivedays followed by a period of about 28 days or longer with no BrEAtreatment. The patients were them provided with one more course of 5consecutive days of dosing with BrEA, followed by a non-dosing period ofat least about 28 days. Up to 5 rounds of 5-day treatments, followed byat least 28 days of no dosing were provided. Immunological responseswere then assayed using blood or plasma samples from the patients byflow cytometry and other known analytical methods. Immune cell subsetsor other measured markers were assayed within 24 hours of obtaining thesample from each patient. Labeled antibodies, e.g., anti-CD antigenantibodies conjugated with fluorescent dyes (FITC, phycoerythrin,allophycocyanin or PerCP), were prepared and used essentially accordingto standard protocols using commercially available reagents, see, e.g.,PharMingen, 1998 Research Products Catalog, technical protocols at pages732-774, human cell surface molecules at pages 182-295 and mouse, ratand hamster cell surface molecules at pages 2-173 and cytokine andchemokine reagents at pages 344-489.

[0924] The clinical protocol is a phase I/II, open-label, randomizedstudy of 3 dose levels of BrEA administered intramuscularly toHIV-infected patients who are treatment naive. There will be 3 treatmentgroups and each group will consist of 2 parts (Parts A and B). Patientswill receive the same dosage of BrEA throughout Parts A and B of thestudy. If a patient experiences an antiviral response (an HIV RNA titerat least 0.5 log below the average of the screening and baseline values)or benefits (any decrease in HIV RNA titers below the average of thescreening and baseline values) from the treatment received during PartsA and B of the study, the patient may continue receiving 5-day treatmentcourses of the BrEA formulation of example 2 at the dose initiallyreceived. This treatment course may be repeated up to six times.

[0925] All patients may be monitored for levels of HIV RNA (ChironQuantiplex™ branched chain DNA assay), T-cell subsets [CD4/CD8],proviral HIV DNA (PBMC), interleukins [IL-2, 4, 6, 8, 10, and 12](serum), γIFN (serum), insulin-like growth factor [IGF-1] (serum) andtumor necrosis factor [TNF] (serum) throughout the study. PBMCquantitative co-culture (cells) may be conducted on a subset of patientsamples. Assays for additional activation markers may be conducted.Analysis of chemistry and hematology panels and urinalysis is planned.Additionally, patients co-infected with hepatitis B and/or C viruses,malaria or tuberculosis may be monitored regularly for viral titers ormicrobiological cultures. Serial blood and urine samples will becollected from a subset of patients for pharmacokinetic determinationafter the first dose on Part A and the last dose on Part B.

[0926] Treatment may consist of more than one intramuscular injection.Intramuscular injections may be administered in different locations(i.e., left or right upper arms or thighs or buttocks) and a single 100mg or 200 mg dose of BrEA may be delivered to patients in two or moresubdoses of less than 100 mg (e.g., 50 mg).

[0927] There are two segments of this study, Segment 1 and 2. Bothsegments consist of two parts, Part A and Part B. The first 12 patientsenrolled on the study will be assigned to the design described inSegment 1. The remaining 24 patients will be assigned to Segment 2 ofthe study. The design of each segment is provided below.

[0928] Part A will consist of a single intramuscular injection of a BrEAformulation. The day the patient receives the injection will be studyday 1. Patients participating in the pharmacokinetic subgroup will haveserial blood and urine samples collected, beginning on study day 1. PartB of the study begins on study day 8 (Segment 1) or study day 15(Segment 2).

[0929] Segment 1 Part B consists of 5 consecutive daily intramuscularinjections of the formulation of example 1 at the same dose as receivedin Part A of the study. The day the patient receives the first dose willbe on about study day 8-12. The 5-day treatment course is followed by anapproximate 28-day observation period (or approximately 32 days from afirst dose on day 8 to the initiation of a second treatment course onday 40). During the observation period, patients will be asked to returnto the clinic on a weekly basis for various tests. Patientsparticipating in the pharmacokinetic subgroup will have serial blood andurine samples collected, beginning approximately on study day 12-17.

[0930] Segment 2 Part B consists of 5 consecutive daily intramuscularinjections of the formulation of example 2 at the same dose the patientreceived during Part A of the study. The day the patient receives thefirst dose will be about at study day 15. The 5-day treatment course isfollowed by an approximate 45 day observation period (or approximately49 days from the first dose on study day 15 to the initiation of thenext treatment course on study day 64). During the observation period,patients will be asked to return to the clinic on a weekly basis forvarious tests. Patients participating in the pharmacokinetic subgroupwill have serial blood and urine samples collected, beginningapproximately on study day 19.

[0931] Randomization in this dose escalation study is as follows. When 4of the 12 patients per treatment group have completed 5 days of dailydosing on Part B and have not experienced a serious drug-related adverseevent, enrollment into the next higher dose level will occur, afterconsultation between the sponsor and investigators.

[0932] The first four patients enrolled will be assigned to the 50 mgdose group. If no serious drug-related adverse events are experienced,the next 8 subjects will be randomized to either the 50 mg or 100 mgdose level in a 1:1 fashion. If no serious drug-related adverse eventsoccur in patients receiving 100 mg, then the next 24 patients will berandomized to either the 50, 100, or 200 mg dose group in a 1:2:3fashion.

[0933] If 4 of the 12 patients in a dose group experiences a seriousdrug-related event (Grade III or IV), 2 additional patients will beenrolled at the same dose level. Additionally, patient enrollment on tothe next dose level, if enrolling, will be temporarily on hold untilsafety is assessed. If one of the 2 additional patients experiences aserious drug-related event, dosing in this dose level will discontinue.Upon consultation with the sponsor and investigators, additionalpatients may be enrolled at a dose between the dose-limiting group andthe next lower dose group to determine the maximum tolerated dose (MTD).Enrollment of additional patients at a specific dose level will bedetermined in a protocol amendment.

[0934] The results indicated that a single 50 mg or 100 mg dose of BrEAincreased the numbers of activated CD8⁺ and CD4⁺ T cells (e.g., CD8⁺,CD69⁺, CD25⁻ cells) that were circulating in the patient's blood. Also,the circulating numbers of dendritic precursor cells, NK cells, LAKcells and cells that mediate ADCC (antibody-dependent cell-mediatedcytotoxicity mediated by the CD8⁺, CD16⁻ immune cell subset) functionswere increased. Further increases were usually observed on dosing for 5consecutive days.

[0935] Some of the results are summarized below. Course 1, 2 and 3 referto each 5 consecutive day treatment regimen of one daily injection withBrEA (50 or 100 mg BrEA per injection). In the diagrams below, HE2000refers to the formulation containing 100 mg/mL BrEA, PEG300 ˜30% v/v,propylene glycol 30% v/v, benzyl benzoate 30% v/v and benzyl alcohol 2%v/v. The data shown below was obtained from patient blood samples atbaseline (on the day dosing was initiated) and at various times afterthe patients received at least one dose of BrEA. The results showedsignificant increases in immune cell populations and cytokine expressionprofiles associated with Th1 responses. The patients in this protocolinitially had CD4 counts of at least 200 per mm³ and a serum HIV RNAload of 5,000 to 1×10⁶ RNA copies/mL. After dosing with one course ofBrEA (5 consecutive daily i.m. injections), all patients showedincreases in levels of immune cells including activated CD8 T cells(e.g., CD8⁺, CD69⁺, CD25⁻), LAK cells (e.g., CD8⁺, CD16⁺, CD38⁺), NKcells (e.g., CD8⁻, CD16⁺), ADCC cells (e.g., CD8^(−, CD)16⁺) anddendritic cells (Lin⁻, HLA-DR⁺, CD11⁺ or Lin⁻, HLA-DR⁺, CD123⁺). AverageCD4 IL-10 production dropped from a median of 66% to 4% of the cells,while CD4 IFNγ went from a median of 8% to 63%, leading to a Th2 to aTh1 shift in cytokine production.

[0936] In the diagrams below baseline data is indicated by “BL” or by“pre”. Increased immunophenotypes after BrEA therapy PhenotypeBaseline^(a) Course 1 Course 2 Course 3 CD8+CD69+CD25− 18 54 56 75 n=(13)  (13)  (9)  (4)  ^(b)p= <0.001 <0.001 0.04 CD8+CD16+CD38+ 8 27 2825 n= (10)  (10)  (4)  (4)  p= <0.001 0.047 0.02 CD8−CD16+ 53 253 288249 n= (12)  (12)  (4)  (2)  p= <0.001 0.02 0.04 Lin−HLA−DR+ 3.2 17.7 11.4^(c)  14.7^(c) CD11c+/CD123+ n= (10)  (10)  (5)  (4)  p= <0.0010.02 0.04 IL2+CD4^(d)   3.14^(e) 29.25 31.42 13.59 n= 13 13 3 4 p=<0.001 0.09 0.04 IL10+CD4^(d) 66 20.9 8.9 15.3 n= 13 13 5 3 p= 0.0050.005 0.03 Th1 Response^(d) 17 66 64 53 n= (13)  (13)  (5)  (5)  p=0.001 0.033 0.025

[0937]

[0938] received 60 mg of BrEA in 1.5 mL daily for 10 days. During theperiod of dosing, the diarrhea ceased. After the 1 0-day dosing periodended, diarrhea resumed. In other patients receiveing oral BrEA,diarrhea also went into remission.

Example 22 Subcutaneous Formulation

[0939] A BrEA formulation was prepared essentially as described herein.The formulation contained 50 mg/mL BrEA, 40% v/v PEG 200, 2% v/v benzylalcohol, 2% v/v benzyl benzoate and ˜66% v/v propylene glycol (qs). Theformulation is particularly suitable for subcutaneous administration ofthe compound.

Example 23 Preparation of BrEA Hemihydrate—Procedure 1

[0940] Crude BrEA was prepared by bromination of epiandrosterone,followed by crystallization from methanol. The hemihydrate was preparedby dissolving 25 g of crude BrEA in 75 mL of refluxing ethanol withmoderate agitation. To the BrEA solution 12.5 mL of water was slowlyadded while maintaining the solution at reflux with agitation. Agitationof the solution was maintained and the solution was then allowed to coolto about 20-25° C. and kept at about 20-25° C. for about 15 minutes toobtain a suspension of BrEA hemihydrate crystals. The crystals wererecovered by filtration, washed with a solution of 25 mL ofwater:ethanol (5:1 v/v) at about 20-25° C. and then vacuum dried forabout 13 hours at 50-60° C. until the product weight was constant. Thecrystals were primarily rod and needle shaped, with smaller amounts ofother shapes such as tablets.

[0941] The procedure gave 22.5 g of BrEA hemihydrate (yield 90%) with awater content of 2.6% w/w by KF analysis, a purity of 100% by HPLC areaanalysis, an FTIR spectrum with carbonyl peaks at 1741 cm⁻¹ and 1752cm⁻. The FTIR scan of anhydrous BrEA shows a single carbonyl peak at1749 cm⁻¹. The DSC scan showed three endotherms. One had a broad shallowpeak with an onset at about 109-110° C. and ending at about 150° C. Thisbroad DSC peak is consistent with the loss of water from the hemihydratecrystals as the temperature of the sample increased. The secondendotherm at about 83-100° C. is consistent with the loss of the smallamount of residual ethanol from the sample. A DSC scan of anhydrous BrEAdoes not have the broad endotherm that is observed with the hemihydrate.Also consistent with the loss of water from the hemihydrate over the100-150° C. range is a sharp third endotherm peak in the hemihydrate DSCscan at about 163-164° C., which is the melting point of anhydrous BrEA.The FTIR was obtained using USP method <197>, where the BrEA hemihydratesample was prepared in KBr. The DSC thermogram was obtained by scanningfrom 25° C. to 250° C. with a heating rate of 10° C./minute.

Example 24 Preparation of BrEA Hemihydrate—Procedure 2

[0942] The hemihydrate was prepared by dissolving 10 g of crude BrEA in40 mL of refluxing acetone with moderate agitation. To the BrEA solution4.0 mL of water was slowly added while maintaining the solution atreflux with agitation. Agitation of the solution was maintained and thesolution was then allowed to cool to about 20-25° C. and kept at about20-25° C. for about 15 minutes to obtain a suspension of BrEAhemihydrate crystals. The crystals were recovered by filtration, washedwith a solution of 6.0 mL of water:acetone (10:1 v/v) at about 20-25° C.and then vacuum dried overnight (about 13-15 hours) at 50-60° C. untilthe product weight was constant. The procedure gave 7.0 g of BrEAhemihydrate (yield 70%) with a water content of 2.6% w/w by KF analysisand an FTIR spectrum with carbonyl peaks at 1741 cm⁻¹ and 1752 cm⁻¹.

Example 25 Analysis of BrEA Hemihydrate Particle Size

[0943] BrEA hemihydrate crystals were prepared essentially as describedherein and sized using a particle sizing apparatus (MalvernInstruments). The analysis model used was for a polydisperse sample anda volume distribution type. The analysis showed a range of crystaldiameter sizes from about 0.5 μm to about 880 μm. About 90% of thecrystals had a diameter of about 20 μm to about 220 μm and the majorityof the crystals had a diameter of about 30-200 μm. The mean crystaldiameter was about 93 μm. The specific surface area of the crystals wasabout 0.25 m²/g.

[0944] To the extent not already indicated, it will be understood bythose of ordinary skill in the art that any of the various specificembodiments, compounds or compositions described herein may be furthermodified to incorporate other appropriate features, e.g., as shown inany other of the specific embodiments disclosed herein or in the citedreferences.

What is claimed is:
 1. A method to treat a subject having, or susceptible to developing, a pathogen infection, an autoimmune disease, inflammation or allergy, osteoporosis, acute myelitis, sarcoidosis, a cancer, a precancer, a neurological disorder, a wound, a bone fracture, a hemorrhage, a burn, a skin lesion or an immunosuppression condition or an unwanted immune response either or both of which are associated with a chemotherapy, radiation exposure or aging, wherein the method comprises intermittent administration of an effective amount of a compound to the subject, wherein the compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate or the compound has the structure

wherein, the dotted lines are optional double bonds and the hydrogen atom at the 5-position, if present, is in the α-configuration; R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁰ independently are —H, —OH, —OR^(PR), —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or, one more of R², R³, R⁴, R⁵, R⁶, R¹⁰, R¹⁵, R¹⁷ and R¹⁸ independently are ═O, or, R³ and both R⁴ together comprise a structure of formula 2

R⁷ is —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —CHR¹⁰—CHR¹⁰—CHR¹⁰—, —CHR¹⁰—O—CHR¹⁰—, —CHR¹⁰—S—CHR¹⁰—, —CHR¹⁰—NR^(PR)—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—; R⁸ and R⁹ independently are —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, or R⁸ or R⁹ independently is absent, leaving a 5-membered ring; R¹³ independently are C₁₋₆ alkyl; R^(PR) independently are a protecting group; D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are optionally independently substituted with —O—, —S— or —NR^(PR)— or where 1, 2 or 3 hydrogen atoms of the heterocycle or 1 or 2 hydrogen atoms of the 4-, 5-, 6- or 7-membered ring are substituted with —OR^(PR), —SR^(PR), —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or, one more of the ring carbons are substituted with ═O or ═S, or D comprises two 5- or 6-membered rings, wherein the rings are fused or are linked by 1 or 2 bonds, provided that the compound is not 3β-hydroxyandrost-5-ene-17-one, 3β-hydroxyandrost-5-ene-1 7-one 3-sulfate or an ester or ether derivative of either compound and provided that when the compound has the structure

wherein each R^(A) independently is —OH, ═O, an ester or an ether, and R^(B) is —C(O)CH₃, —OH, ═O, an ester or an ether, then the use of the medicament is for the treatment of a subject having or susceptible to developing an autoimmune disease, inflammation or allergy, osteoporosis, acute myelitis, sarcoidosis, a cancer, a precancer, or an immunosuppression condition or an unwanted immune response either or both of which are associated with a chemotherapy, radiation exposure, a wound, a bone fracture, a hemorrhage, a skin lesion or a burn or the medicament is for the treatment of a human having or susceptible to developing a pathogen infection selected from the group consisting of HIV-1, HIV-2, HTLV-1, HTLV-2, HSV-1, HSV-2, HHV-6, HHV-8, CMV, hepatitis C virus, hepatitis B virus, Western Equine Encephalitis Virus, Japanese Encephalitis Virus, Yellow Fever Virus, a poxvirus, a Dengue virus, a papillomavirus, a togavirus, a flavivirus, an intracellular bacterium, Mycobacterium, Listeria, Brucella, Bartonella, Bordetella, Pseudomonas, Yersinia, Vibrio, Salmonella, Streptococcus, Staphylococcus, Candida, Aspergillus, Cryptococcus, Plasmodium, Trypanosoma, Leishmania, a gastrointestinal nematode, a helminth, Cryptosporidium, Toxoplasma, Pneumocystis, Schistosoma, or Strongyloides stercoralis.
 2. The method of claim 1 wherein the compound has the structure

wherein, hydrogen atoms at the 5 (if present), 8, 9 and 14 positions respectively in the α,α,α,α, α,α,α,β, α,α,β,α, α,β,α,α, α,α,β,β, α,β,α,β, α,β,β,α or α,β,β,β configurations.
 3. The method of claim 2 wherein hydrogen atoms at the 5 (if present), 8, 9 and 14 positions respectively are in the α,β,α,α configurations.
 4. The method of claim 1 wherein (1) R³ is a halogen and R¹, R², and one or both R⁴ independently are —OH, —OR^(PR), an ether an ester having the structure steroid-O—C(O)-organic moiety, carbonate, carbamate having the structure steroid-O—C(O)—NR^(PR)-organic moiety, or an amino acid ester or peptide having the structure (A) R³²—NH—{[C(R²⁹)(R³⁰)]_(b)—C(O)—N(R³¹)}_(f)—[C(R²⁹)(R³⁰)]_(a)—C(O)—O-steroid, (B) R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(g)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—O—steroid, or (C) R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(e)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—C(O)—O-steroid, where each R²⁹, R³⁰ and R³¹ is independently selected and each R²⁹ independently is —H or a C1-20 organic moiety, each R³⁰ independently is the side chain of an amino acid, each R³¹ is —H or a protecting group, R³² and R³³ independently are —H, a protecting group, an ester or an amide where each atom or group is independently chosen, a, b, c and d independently are 1, 2, 3, 4 or 5, and e, f and g independently are an integer from 0 to 1000, or (2) R¹, R², R³ and one or both R⁴ independently are —OH, —OR^(PR), an ether, an ester having the structure steroid-O—C(O)-organic moiety, carbonate, carbamate having the structure steroid-O—C(O)—NR^(PR)-organic moiety or an amino acid or peptide having the structure (A) R³²—NH—{[C(R²⁹)(R³⁰)]_(b)—C(O)—N(R³¹)}_(f)-[C(R²⁹)(R³⁰)]_(a)—C(O)—O-steroid, (B) R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N (R³¹)}_(g)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—O-steroid, or (C) R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(e)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—C(O)—O-steroid, or (3) R¹ is −H and R², R³ and one or both R⁴ are not —H, provided that the compound is not 7α,17α-methyl-16-methylene-17β-hydroxy-19-norandrost-4-ene, 7α-methyl-16-methylene-17β-hydroxy-17α-ethynyl-19-norandrost-4-ene or 7α-methyl-16-methylene-17-oxo-19-norandrost-4-ene or an ester or ether of any of these compounds, or (4) R¹ is —CN, ═CH₂, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, ester having the structure steroid-C(O)—O-organic moiety, thioester having the structure steroid-C(S)—O-organic moiety or thioacetal having the structure steroid-C(O)—S-organic moiety, and R³ and one or both R⁴ are not —H, provided that R¹ is not optionally substituted phenyl and provided that if R¹ is —C(O)—OCH₃, then R⁴ is not —CH₃ or —C(O)—CH₃, or (5) R¹ is a halogen and R³ and one or both R⁴ are not —H, provided that either R³ is —OH, —OR^(PR), an ether, an ester having the structure steroid-O—C(O)-organic moiety, carbonate (O—C(O)—O—), carbamate, a halogen, —NH₂, —N(R^(PR))₂, —NO₂, —N₃, ═NOH, ═NOC(O)CH₃, an amide, —SH, —SR^(PR), ═S, thioether, thioacetal —CN, acyl, thioacyl, or an amino acid or peptide having the structure (A) R³²—NH—{[C(R²⁹)(R³⁰)]_(b)—C(O)—N(R³¹)}_(f)—[C(R²⁹)(R³⁰)]_(a)—C(O)—O-steroid, (B) R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(g)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—O-steroid, or (C) R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(e)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—C(O)—O-steroid, or one or both R⁴ independently are —OH, —OR^(PR), an ether, an ester having the structure steroid-O—C(O)-organic moiety, carbonate, carbamate, a halogen, —NH₂, —N(R^(PR))₂, —NO₂, —N₃, ═NOH, ═NOC(O)CH₃, amide having the structure steroid-NR^(PR)—C(O)-organic moiety, —SH, —SR^(PR), ═S, thioether, thioacetal having the structure steroid-S—C(O)-organic moiety, —CN, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, ester having the structure steroid-O—C(O)-organic moiety, thioester having the structure steroid-O—C(S)-organic moiety, thioacetal having the structure steroid-S—C(O)-organic moiety, or an amino acid or peptide having the structure (A) R³²—NH—{[C(R²⁹)(R³⁰)]_(b)—C(O)—N(R³¹)}_(f)—[C(R²⁹)(R³⁰)]_(a)—C(O)—O-steroid, (B) R³³—O-{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹ )}_(g)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—O-steroid, or (C) R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(e)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹ )—C(O)—O-steroid, or (6) R¹ is a halogen, —NH₂, —N(R^(PR))₂, —NO₂, ═NOH, ═NOC(O)CH₃, amide having the structure steroid-NR^(PR)—C(O)-organic moiety, carbamate having the structure steroid-NR^(PR)—C(O)—O-organic moiety, —SH, —SR^(PR), ═S, thioether, thioacetal having the structure steroid-S—C(O)-organic moiety, —CN, ═CH₂, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, ester having the structure steroid-C(O)—O-organic moiety, thioester having the structure steroid-C(S)—O-organic moiety or thioacetal having the structure steroid-C(O)—S-organic moiety and R², R³ and one or both R⁴ are not —H, or (7) R¹ is a halogen, —NH₂, —NO₂, —N₃, ═NOH, ═NOC(O)CH₃, amide having the structure steroid-NR^(PR)—C(O)-organic moiety, carbamate having the structure steroid-NR^(PR)—C(O)—O-organic moiety, —SR^(PR), thioether, thioacetal having the structure steroid-S—C(O)-organic moiety, —CN, ═CH₂, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, ester having the structure steroid-C(O)—O-organic moiety, thioester having the structure steroid-C(S)—O-organic moiety, or thioacetal having the structure steroid-C(O)—S-organic moiety and R² and one or both R⁴ are not —H and R⁹ is not —CH₂—, provided that if one R⁴ is —CH₂CH₃, then R³ is not ═O, or (8) R¹ is a halogen, —NH₂, —N(R^(PR))₂, —NO₂, —N₃, ═NOH, ═NOC(O)CH₃, amide having the structure steroid-NR^(PR)—C(O)-organic moiety, carbamate having the structure steroid-NR^(PR)—C(O)—O-organic moiety, —SR^(PR), thioether, thioacetal having the structure steroid-S—C(O)-organic moiety, —CN, ═CH₂, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, ester having the structure steroid-C(O)—O-organic moiety, thioester having the structure steroid-C(S)—O-organic moiety, or thioacetal having the structure steroid-C(O)—S-organic moiety and R² and one or both R⁴ are not —H and R⁷ is not —CH₂—, or (9) R¹ is a halogen, —NH₂, —N(R^(PR))₂, —NO₂, —N₃, ═NOH, ═NOC(O)CH₃, amide having the structure steroid-NR^(PR)—C(O)-organic moiety, carbamate having the structure steroid-NR^(PR)—C(O)—O-organic moiety, —SR^(PR), thioether, thioacetal having the structure steroid-S—C(O)-organic moiety, —CN, ═CH₂, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, ester having the structure steroid-C(O)—O-organic moiety, thioester having the structure steroid-C(S)—O-organic moiety, or thioacetal having the structure steroid-C(O)—S-organic moiety and R² and one or both R⁴ are not —H, and R⁶ is not —CH₃, provided that R¹ is not fluorine if R² is ═O, one R⁴ is —OH or —O—C(O)—CH₃ and R⁶ is —CH₂OH or —CH₂O—C(O)—CH₃, or (10) R¹ is —H, R² and one or both R⁴ are not —H and R⁹ is not —CH₂—, provided that R⁹ is not —C(O)— or —CH(OH)— when R² is —OH in the α-configuration, both R⁴ are —H and alkyl and a double bond is present at the 4-5 position, or (11) R¹ is —H, R² is not —H and R⁸ and R⁹ are not —CH₂—, or (12) R¹ is a halogen, —NH₂, —N(RPR)₂, —NO₂, —N₃, ═NOH, ═NOC(O)CH₃, amide having the structure steroid-NR^(PR)—C(O)-organic moiety, carbamate having the structure steroid-NR^(PR)—C(O)—O-organic moiety, —SH, —SR^(PR), ═S, thioether, thioacetal having the structure steroid-S—C(O)-organic moiety, —CN, ═CH₂, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, ester having the structure steroid-C(O)—O-organic moiety, thioester having the structure steroid-C(S)—O-organic moiety, or thioacetal having the structure steroid-C(O)—S-organic moiety and R³ and one or both R⁴ are not —H, and R⁶ is not —CH₃, or (13) the compound has the structure

wherein R¹ is —OH, —OR^(PR), —SH, —SR^(PR), —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, R² is —H, —OH, —OR^(PR), —SH, —SR^(PR), ═S, —CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, R³ is —OH, —OR^(PR), —SH, —SRPR, ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, provided that the compound is not 3α-bromo-16α-methoxyandrost-5-ene-17-one, and R⁴ is —H, —OH, —OR^(PR), —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or (14) the compound has the structure

wherein R¹ is —OH, —OR^(PR), —SH, —SR^(PR), —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, R² is —OH, —OR^(PR), —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, and R³ is —H, —OH, —OR^(PR), —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, provided that the compound is not 3α-bromo-16α-methoxyandrost-5-ene-17-one, and R⁴ is —H, —OH, —OR^(PR), —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(RPR)₂, —O— Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or (15) R¹ is a halogen, —NH₂, —N(RPR)₂, —NO₂, —N₃, ═NOH, amide having the structure steroid-NR^(PR)—C(O)-organic moiety, carbamate having the structure steroid-NR^(PR)—C(O)—O-organic moiety, —SR^(PR), thioether, thioacetal having the structure steroid-S—C(O)-organic moiety, —CN, ═CH₂, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, ester having the structure steroid-C(O)—O-organic moiety, thioester having the structure steroid-C(S)—O-organic moiety, or thioacetal having the structure steroid-C(O)—S-organic moiety and R², one or both R⁴ and R⁷ are not —H or —CH₂—, provided that if R¹ is —NH₂ or —N(R^(PR))₂, then R² is not methyl, or (16) R¹ is —H and R³, one or both R⁴ are not —H and R⁵ is not —CH₂—, or (17) R¹ is —H and R³, one or both R⁴ are not —H and R⁹ is not —CH₂—, or (18) R¹ is —H and R², one or both R⁴ are not —H and R⁸ is not —CH₂—, or (19) R¹ is a halogen, R² and R⁸ are not —H or —CH₂— and one or both R⁴ independently are —OR^(PR), ether, an ester having the structure steroid-O—C(O)-organic moiety, carbonate (O—C(O)—O—), carbamate having the structure steroid-O—C(O)—NR^(PR)-organic moiety, optionally substituted monosaccharide, optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide, a polymer, or an amino acid or peptide having the structure (A) R³²—NH—{[C(R²⁹)(R³⁰)]_(b)—C(O)—N(R³¹)}_(f)—[C(R²⁹)(R³⁰)]_(a)—C(O)—O-steroid, (B) R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(g)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—O-steroid, or (C) R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹ )}_(e)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—C(O)—O-steroid.
 5. The method of claim 4 wherein hydrogen atoms at the 5 (if present), 8, 9 and 14 positions respectively are in the α,β,α,α configurations.
 6. The method of claim 1 wherein the compound has the structure

wherein, R⁵ and R⁶ independently are —CH₃, —H or —CH₂OH, R⁷, R⁸ and R⁹ independently are —CH₂—, —O—, —NH— or —S—, R¹, R², R³ and R⁴ respectively are in the β,β,α,β, α,β,α,β, β,α,α,β, β,β,β,β, or β,β,α,α configurations and the compound's structure is designated by numbers assigned to R¹, R², R³ and R⁴ according to the convention, R¹.R².R³.R⁴, wherein the structures for R¹, R², R³ and R⁴ are designated by numbers respectively and, for R¹, structure 1 is —OH, structure 3 is —SH, structure 4 is ═S, structure 5 is —OCH₃, structure 6 is —O—S(O)(O)—O—Na⁺, structure 7 is —O—S(O)(O)—OC₂H₅, structure 8 is —CH₃, structure 9 is —H, and structure 10 is —OC(O)C(CH₃)₃, and for R², structure 1 is —H, structure 2 is —OH, structure 3 is ═O, structure 4 is —CH₃, structure 5 is —OCH₃, structure 6 is -OC₂H₅, structure 7 is —OCH₂CH₂CH₃, structure 8 is —OCH₂CH₂CH₂CH₃, structure 9 is —Cl, and structure 10 is —Br, and for R³, structure 1 is —Br, structure 2 is —Cl, structure 3 is —I, structure 4 is —F, structure 5 is —H, structure 6 is —OH, structure 7 is =O, structure 8 is —OC(O)CH₃, structure 9 is —OC(O)CH₂CH₃, and structure 10 is —OC(O)CH₂CH₂CH₃, and for R⁴, structure 1 is ═O, structure 2 is —OH, structure 3 is —H, structure 4 is —F, structure 5 is —Cl, structure 6 is —Br, structure 7 is —I, structure 8 is —OC(O)CH₃, structure 9 is —OC(O)CH₂CH₃, and structure 10 is —OC(O)CH₂CH₂CH₃, wherein the compound is 1.1.1.1, 1.1.1.2, 1.1.1.3, 1.1.1.4, 1.1.1.5, 1.1.1.6, 1.1.1.7, 1.1.1.8, 1.1.1.9, 1.1.1.10, 1.1.2.1, 1.1.2.2, 1.1.2.3, 1.1.2.4, 1.1.2.5, 1.1.2.6, 1.1.2.7, 1.1.2.8, 1.1.2.9, 1.1.2.10, 1.1.3.1, 1.1.3.2, 1.1.3.3, 1.1.3.4, 1.1.3.5, 1.1.3.6, 1.1.3.7, 1.1.3.8, 1.1.3.9, 1.1.3.10, 1.1.4.1, 1.1.4.2, 1.1.4.3, 1.1.4.4, 1.1.4.5, 1.1.4.6, 1.1.4.7, 1.1.4.8, 1.1.4.9, 1.1.4.10, 1.1.5.1, 1.1.5.2, 1.1.5.3, 1.1.5.4, 1.1.5.5, 1.1.5.6, 1.1.5.7, 1.1.5.8, 1.1.5.9, 1.1.5.10, 1.1.6.1, 1.1.6.2, 1.1.6.3, 1.1.6.4, 1.1.6.5, 1.1.6.6, 1.1.6.7, 1.1.6.8, 1.1.6.9,1.1.6.10, 1.1.7.1, 1.1.7.2, 1.1.7.3, 1.1.7.4, 1.1.7.5, 1.1.7.6, 1.1.7.7, 1.1.7.8, 1.1.7.9, 1.1.7.10, 1.1.8.1, 1.1.8.2, 1.1.8.3, 1.1.8.4, 1.1.8.5, 1.1.8.6, 1.1.8.7, 1.1.8.8, 1.1.8.9, 1.1.8.10, 1.1.9.1, 1.1.9.2, 1.1.9.3, 1.1.9.4, 1.1.9.5, 1.1.9.6, 1.1.9.7, 1.1.9.8, 1.1.9.9, 1.1.9.10, 1.1.10.1, 1.1.10.2, 1.1.10.3, 1.1.10.4, 1.1.10.5, 1.1.10.6, 1.1.10.7, 1.1.10.8, 1.1.10.9, 1.1.10.10, 1.2.1.1, 1.2.1.2, 1.2.1.3, 1.2.1.4, 1.2.1.5, 1.2.1.6, 1.2.1.7, 1.2.1.8, 1.2.1.9, 1.2.1.10, 1.2.2.1, 1.2.2.2, 1.2.2.3, 1.2.2.4, 1.2.2.5, 1.2.2.6, 1.2.2.7, 1.2.2.8, 1.2.2.9, 1.2.2.10, 1.2.3.1, 1.2.3.2, 1.2.3.3, 1.2.3.4, 1.2.3.5, 1.2.3.6, 1.2.3.7, 1.2.3.8, 1.2.3.9, 1.2.3.10, 1.2.4.1, 1.2.4.2, 1.2.4.3, 1.2.4.4, 1.2.4.5, 1.2.4.6, 1.2.4.7, 1.2.4.8, 1.2.4.9, 1.2.4.10, 1.2.5.1, 1.2.5.2, 1.2.5.3, 1.2.5.4, 1.2.5.5, 1.2.5.6, 1.2.5.7, 1.2.5.8, 1.2.5.9, 1.2.5.10, 1.2.6.1, 1.2.6.2, 1.2.6.3, 1.2.6.4, 1.2.6.5, 1.2.6.6, 1.2.6.7, 1.2.6.8, 1.2.6.9, 1.2.6.10, 1.2.7.1, 1.2.7.2, 1.2.7.3, 1.2.7.4, 1.2.7.5, 1.2.7.6, 1.2.7.7, 1.2.7.8, 1.2.7.9, 1.2.7.10, 1.2.8.1, 1.2.8.2, 1.2.8.3, 1.2.8.4, 1.2.8.5, 1.2.8.6, 1.2.8.7, 1.2.8.8, 1.2.8.9, 1.2.8.10, 1.2.9.1, 1.2.9.2, 1.2.9.3, 1.2.9.4, 1.2.9.5, 1.2.9.6, 1.2.9.7, 1.2.9.8, 1.2.9.9, 1.2.9.10, 1.2.10.1, 1.2.10.2, 1.2.10.3, 1.2.10.4, 1.2.10.5, 1.2.10.6, 1.2.10.7, 1.2.10.8, 1.2.10.9, 1.2.10.10, 1.3.1.1, 1.3.1.2, 1.3.1.3, 1.3.1.4, 1.3.1.5, 1.3.1.6, 1.3.1.7, 1.3.1.8, 1.3.1.9, 1.3.1.10, 1.3.2.1, 1.3.2.2, 1.3.2.3, 1.3.2.4, 1.3.2.5, 1.3.2.6, 1.3.2.7, 1.3.2.8, 1.3.2.9, 1.3.2.10, 1.3.3.1, 1.3.3.2, 1.3.3.3, 1.3.3.4, 1.3.3.5, 1.3.3.6, 1.3.3.7, 1.3.3.8, 1.3.3.9, 1.3.3.10, 1.3.4.1, 1.3.4.2, 1.3.4.3, 1.3.4.4, 1.3.4.5, 1.3.4.6, 1.3.4.7, 1.3.4.8, 1.3.4.9, 1.3.4.10, 1.3.5.1, 1.3.5.2, 1.3.5.3, 1.3.5.4, 1.3.5.5, 1.3.5.6, 1.3.5.7, 1.3.5.8, 1.3.5.9, 1.3.5.10, 1.3.6.1, 1.3.6.2, 1.3.6.3, 1.3.6.4, 1.3.6.5, 1.3.6.6, 1.3.6.7, 1.3.6.8, 1.3.6.9, 1.3.6.10, 1.3.7.1, 1.3.7.2, 1.3.7.3, 1.3.7.4, 1.3.7.5, 1.3.7.6, 1.3.7.7, 1.3.7.8, 1.3.7.9, 1.3.7.10, 1.3.8.1, 1.3.8.2, 1.3.8.3, 1.3.8.4, 1.3.8.5, 1.3.8.6, 1.3.8.7, 1.3.8.8, 1.3.8.9, 1.3.8.10, 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10.4.8.2, 10.4.8.3, 10.4.8.4, 10.4.8.5, 10.4.8.6, 10.4.8.7, 10.4.8.8, 10.4.8.9, 10.4.8.10, 10.4.9.1, 10.4.9.2, 10.4.9.3, 10.4.9.4, 10.4.9.5, 10.4.9.6, 10.4.9.7, 10.4.9.8, 10.4.9.9, 10.4.9.10, 10.4.10.1, 10.4.10.2, 10.4.10.3, 10.4.10.4, 10.4.10.5, 10.4.10.6, 10.4.10.7, 10.4.10.8, 10.4.10.9, 10.4.10.10, 10.5.1.1, 10.5.1.2, 10.5.1.3, 10.5.1.4, 10.5.1.5, 10.5.1.6, 10.5.1.7, 10.5.1.8, 10.5.1.9, 10.5.1.10, 10.5.2.1, 10.5.2.2, 10.5.2.3, 10.5.2.4, 10.5.2.5, 10.5.2.6, 10.5.2.7, 10.5.2.8, 10.5.2.9, 10.5.2.10, 10.5.3.1, 10.5.3.2, 10.5.3.3, 10.5.3.4, 10.5.3.5, 10.5.3.6, 10.5.3.7, 10.5.3.8, 10.5.3.9, 10.5.3.10, 10.5.4.1, 10.5.4.2, 10.5.4.3, 10.5.4.4, 10.5.4.5, 10.5.4.6, 10.5.4.7, 10.5.4.8, 10.5.4.9, 10.5.4.10, 10.5.5.1, 10.5.5.2, 10.5.5.3, 10.5.5.4, 10.5.5.5, 10.5.5.6, 10.5.5.7, 10.5.5.8, 10.5.5.9, 10.5.5.10, 10.5.6.1, 10.5.6.2, 10.5.6.3, 10.5.6.4, 10.5.6.5, 10.5.6.6, 10.5.6.7, 10.5.6.8, 10.5.6.9, 10.5.6.10, 10.5.7.1, 10.5.7.2, 10.5.7.3, 10.5.7.4, 10.5.7.5, 10.5.7.6, 10.5.7.7, 10.5.7.8, 10.5.7.9, 10.5.7.10, 10.5.8.1, 10.5.8.2, 10.5.8.3, 10.5.8.4, 10.5.8.5, 10.5.8.6, 10.5.8.7, 10.5.8.8, 10.5.8.9, 10.5.8.10, 10.5.9.1, 10.5.9.2, 10.5.9.3, 10.5.9.4, 10.5.9.5, 10.5.9.6, 10.5.9.7, 10.5.9.8, 10.5.9.9, 10.5.9.10, 10.5.10.1, 10.5.10.2, 10.5.10.3, 10.5.10.4, 10.5.10.5, 10.5.10.6, 10.5.10.7, 10.5.10.8, 10.5.10.9, 10.5.10.10, 10.6.1.1, 10.6.1.2, 10.6.1.3, 10.6.1.4, 10.6.1.5, 10.6.1.6, 10.6.1.7, 10.6.1.8, 10.6.1.9, 10.6.1.10, 10.6.2.1, 10.6.2.2, 10.6.2.3, 10.6.2.4, 10.6.2.5, 10.6.2.6, 10.6.2.7, 10.6.2.8, 10.6.2.9, 10.6.2.10, 10.6.3.1, 10.6.3.2, 10.6.3.3, 10.6.3.4, 10.6.3.5, 10.6.3.6, 10.6.3.7, 10.6.3.8, 10.6.3.9, 10.6.3.10, 10.6.4.1, 10.6.4.2, 10.6.4.3, 10.6.4.4, 10.6.4.5, 10.6.4.6, 10.6.4.7, 10.6.4.8, 10.6.4.9, 10.6.4.10, 1 0.6.5.1, 10.6.5.2, 1 0.6.5.3, 10.6.5.4, 10.6.5.5, 10.6.5.6, 10.6.5.7, 10.6.5.8, 10.6.5.9, 10.6.5.10, 10.6.6.1, 10.6.6.2, 10.6.6.3, 10.6.6.4, 10.6.6.5, 10.6.6.6, 10.6.6.7, 10.6.6.8, 10.6.6.9, 10.6.6.10, 10.6.7.1, 10.6.7.2, 10.6.7.3, 10.6.7.4, 10.6.7.5, 10.6.7.6, 10.6.7.7, 10.6.7.8, 10.6.7.9, 10.6.7.10, 10.6.8.1, 10.6.8.2, 10.6.8.3, 10.6.8.4, 10.6.8.5, 10.6.8.6, 10.6.8.7, 10.6.8.8, 10.6.8.9, 10.6.8.10, 10.6.9.1, 10.6.9.2, 10.6.9.3, 10.6.9.4, 10.6.9.5, 10.6.9.6, 10.6.9.7, 10.6.9.8, 10.6.9.9, 10.6.9.10, 10.6.10.1, 10.6.10.2, 10.6.10.3, 10.6.10.4, 10.6.10.5, 10.6.10.6, 10.6.10.7, 10.6.10.8, 10.6.10.9, 10.6.10.10, 10.7.1.1, 10.7.1.2, 10.7.1.3, 10.7.1.4, 10.7.1.5, 10.7.1.6, 10.7.1.7, 10.7.1.8, 10.7.1.9, 10.7.1.10, 10.7.2.1, 10.7.2.2, 10.7.2.3, 10.7.2.4, 10.7.2.5, 10.7.2.6, 10.7.2.7, 10.7.2.8, 10.7.2.9, 10.7.2.10, 10.7.3.1, 10.7.3.2, 10.7.3.3, 10.7.3.4, 10.7.3.5, 10.7.3.6, 10.7.3.7, 10.7.3.8, 10.7.3.9, 10.7.3.10, 10.7.4.1, 10.7.4.2, 10.7.4.3, 10.7.4.4, 10.7.4.5, 10.7.4.6, 10.7.4.7, 10.7.4.8, 10.7.4.9, 10.7.4.10, 10.7.5.1, 10.7.5.2, 10.7.5.3, 10.7.5.4, 10.7.5.5, 10.7.5.6, 10.7.5.7, 10.7.5.8, 10.7.5.9, 10.7.5.10, 10.7.6.1, 10.7.6.2, 10.7.6.3, 10.7.6.4, 10.7.6.5, 10.7.6.6, 10.7.6.7, 10.7.6.8, 10.7.6.9, 10.7.6.10, 10.7.7.1, 10.7.7.2, 10.7.7.3, 10.7.7.4, 10.7.7.5, 10.7.7.6, 10.7.7.7, 10.7.7.8, 10.7.7.9, 10.7.7.10, 10.7.8.1, 10.7.8.2, 10.7.8.3, 10.7.8.4, 10.7.8.5, 10.7.8.6, 10.7.8.7, 10.7.8.8, 10.7.8.9, 10.7.8.10, 10.7.9.1, 10.7.9.2, 10.7.9.3, 10.7.9.4, 10.7.9.5, 10.7.9.6, 10.7.9.7, 10.7.9.8, 10.7.9.9, 10.7.9.10, 10.7.10.1, 10.7.10.2, 10.7.10.3, 10.7.10.4, 10.7.10.5, 10.7.10.6, 10.7.10.7, 10.7.10.8, 10.7.10.9, 10.7.10.10, 10.8.1.1, 10.8.1.2, 10.8.1.3, 10.8.1.4, 10.8.1.5, 10.8.1.6, 10.8.1.7, 10.8.1.8, 10.8.1.9, 10.8.1.10, 10.8.2.1, 10.8.2.2, 10.8.2.3, 10.8.2.4, 10.8.2.5, 10.8.2.6, 10.8.2.7, 10.8.2.8, 10.8.2.9, 10.8.2.10, 10.8.3.1, 10.8.3.2, 10.8.3.3, 10.8.3.4, 10.8.3.5, 10.8.3.6, 10.8.3.7, 10.8.3.8, 10.8.3.9, 10.8.3.10, 10.8.4.1, 10.8.4.2, 10.8.4.3, 10.8.4.4, 10.8.4.5, 10.8.4.6, 10.8.4.7, 10.8.4.8, 10.8.4.9, 10.8.4.10, 10.8.5.1, 10.8.5.2, 10.8.5.3, 10.8.5.4, 10.8.5.5, 10.8.5.6, 10.8.5.7, 10.8.5.8, 10.8.5.9, 10.8.5.10, 10.8.6.1 10.8.6.2, 10.8.6.3, 10.8.6.4, 10.8.6.5, 10.8.6.6, 10.8.6.7, 10.8.6.8, 10.8.6.9, 10.8.6.10, 10.8.7.1, 10.8.7.2, 10.8.7.3, 10.8.7.4, 10.8.7.5, 10.8.7.6, 10.8.7.7, 10.8.7.8, 10.8.7.9, 10.8.7.10, 10.8.8.1, 10.8.8.2, 10.8.8.3, 10.8.8.4, 10.8.8.5, 10.8.8.6, 10.8.8.7, 10.8.8.8, 10.8.8.9, 10.8.8.10, 10.8.9.1, 10.8.9.2, 10.8.9.3, 10.8.9.4, 10.8.9.5, 10.8.9.6, 10.8.9.7, 10.8.9.8, 10.8.9.9, 10.8.9.10, 10.8.10.1, 10.8.10.2, 10.8.10.3, 10.8.10.4, 10.8.10.5, 10.8.10.6, 10.8.10.7, 10.8.10.8, 10.8.10.9, 10.8.10.10, 10.9.1.1, 10.9.1.2, 10.9.1.3, 10.9.1.4, 10.9.1.5, 10.9.1.6, 10.9.1.7, 10.9.1.8, 10.9.1.9, 10.9.1.10, 10.9.2.1, 10.9.2.2, 10.9.2.3, 10.9.2.4, 10.9.2.5, 10.9.2.6, 10.9.2.7, 10.9.2.8, 10.9.2.9, 10.9.2.10, 10.9.3.1, 10.9.3.2, 10.9.3.3, 10.9.3.4, 10.9.3.5, 10.9.3.6, 10.9.3.7, 10.9.3.8, 10.9.3.9, 10.9.3.10, 10.9.4.1, 10.9.4.2, 10.9.4.3, 10.9.4.4, 10.9.4.5, 10.9.4.6, 10.9.4.7, 10.9.4.8, 10.9.4.9, 10.9.4.10, 10.9.5.1, 10.9.5.2, 10.9.5.3, 10.9.5.4, 10.9.5.5, 10.9.5.6, 10.9.5.7, 10.9.5.8, 10.9.5.9, 10.9.5.10, 10.9.6.1, 10.9.6.2, 10.9.6.3, 10.9.6.4, 10.9.6.5, 10.9.6.6, 10.9.6.7, 10.9.6.8, 10.9.6.9, 10.9.6.10, 10.9.7.1, 10.9.7.2, 10.9.7.3, 10.9.7.4, 10.9.7.5, 10.9.7.6, 10.9.7.7, 10.9.7.8, 10.9.7.9, 10.9.7.10, 10.9.8.1, 10.9.8.2, 10.9.8.3, 10.9.8.4, 10.9.8.5, 10.9.8.6, 10.9.8.7, 10.9.8.8, 10.9.8.9, 10.9.8.10, 10.9.9.1, 10.9.9.2, 10.9.9.3, 10.9.9.4, 10.9.9.5, 10.9.9.6, 10.9.9.7, 10.9.9.8, 10.9.9.9, 10.9.9.10, 10.9.10.1, 10.9.10.2, 10.9.10.3, 10.9.10.4, 10.9.10.5, 10.9.10.6, 10.9.10.7, 10.9.10.8, 10.9.10.9, 10.9.10.10, 10.10.1.1, 10.10.1.2, 10.10.1.3, 10.10.1.4, 10.10.1.5, 10.10.1.6, 10.10.1.7, 10.10.1.8, 10.10.1.9, 10.10.1.10, 10.10.2.1, 10.10.2.2, 10.10.2.3, 10.10.2.4, 10.10.2.5, 10.10.2.6, 10.10.2.7, 10.10.2.8, 10.10.2.9, 10.10.2.10, 10.10.3.1, 10.10.3.2, 10.10.3.3, 10.10.3.4, 10.10.3.5, 10.10.3.6, 10.10.3.7, 10.10.3.8, 10.10.3.9, 10.10.3.10, 10.10.4.1, 10.10.4.2, 10.10.4.3, 10.10.4.4, 10.10.4.5, 10.10.4.6, 10.10.4.7, 10.10.4.8, 10.10.4.9, 10.10.4.10, 10.10.5.1, 10.10.5.2, 10.10.5.3, 10.10.5.4, 10.10.5.5, 10.10.5.6, 10.10.5.7, 10.10.5.8, 10.10.5.9, 10.10.5.10, 10.10.6.1, 10.10.6.2, 10.10.6.3, 10.10.6.4, 10.10.6.5, 10.10.6.6, 10.10.6.7, 10.10.6.8, 10.10.6.9, 10.10.6.10, 10.10.7.1, 10.10.7.2, 10.10.7.3, 10.10.7.4, 10.10.7.5, 10.10.7.6, 10.10.7.7, 10.10.7.8, 10.10.7.9, 10.10.7.10, 10.10.8.1, 10.10.8.2, 10.10.8.3, 10.10.8.4, 10.10.8.5, 10.10.8.6, 10.10.8.7, 10.10.8.8, 10.10.8.9, 10.10.8.10, 10.10.9.1, 10.10.9.2, 10.10.9.3, 10.10.9.4, 10.10.9.5, 10.10.9.6, 10.10.9.7, 10.10.9.8, 10.10.9.9, 10.10.9.10, 10.10.10.1, 10.10.10.2, 10.10.10.3, 10.10.10.4, 10.10.10.5, 10.10.10.6, 10.10.10.7, 10.10.10.8, 10.10.10.9 or 10.10.10.10.
 7. The method of claim 6 wherein R¹, R², R³ and R⁴ respectively are in the β,β,α,β configurations.
 8. The method of claim 6 wherein R¹, R², R³ and R⁴ respectively are in the β,β,β,β configurations.
 9. The method of claim 6 wherein R¹, R², R³ and R⁴ respectively are in the α,β,α,β configurations.
 10. The method of claim 6 wherein no double bond is present at the 1-2 or 5-6 positions, R¹, R², R³ and R⁴ respectively are in the β,β,α,β configurations, R⁵ and R⁶ are —CH₃ and R⁷, R⁸ and R⁹ are —CH₂—.
 11. The method of claim 6 wherein no double bond is present at the 1-2 position, a double bond is present at the 5-6 position, R¹, R², R³ and R⁴ respectively are in the β,β,α,β configurations, R⁵ and R⁶ are —CH₃ and R⁷, R⁸ and R⁹ are —CH₂—.
 12. The method of claim 6 wherein no double bond is present at the 1-2 position, a double bond is present at the 5-6 position, R¹, R², R³ and R⁴ respectively are in the β,α,α,β configurations, R⁵ and R⁶ are —CH₃ and R⁷, R⁸ and R⁹ are —CH₂—.
 13. The method of claim 6 wherein no double bond is present at the 5-6 position, a double bond is present at the 1-2 position, R¹, R², R³ and R⁴ respectively are in the α,β,α,β configurations, R⁵ and R⁶ are —CH₃ and R⁷, R⁸ and R⁹ are —CH₂—.
 12. The method of claim 6 wherein R⁸ is —O— or —NH— and R⁷ and R⁹ are —CH₂—.
 13. The method of claim 6 wherein R⁹ is —O— or —NH— and R⁷ and R⁸ are —CH₂—.
 14. The method of claim 6 wherein R⁷, R⁸ and R⁹ are —CH₂— and no double bond is present at the 1-2 or 5-6 positions.
 15. The method of claim 6 wherein R⁷, R⁸ and R⁹ are —CH₂—, no double bond is present at the 1-2 position and a double bond is present at the 5-6 position.
 16. The method of claim 6 wherein R⁷, R⁸ and R⁹ are —CH₂—, a double bond is present at the 1-2 position and no double bond is present at the 5-6 position.
 17. The method of claim 6 wherein the compound is 16β-bromo-3β-hydroxy-5α-androstan-17-one, 16α-bromo-3β-hydroxy-5α-androstan-17-one, 3β,16β-dihydroxy-5α-androstan-17-one, 3β,16β-dihydroxy-5α-androstan-17-one, 3β,16α,17β-trihydroxy-5α-androstane, 3β,16β,17β-trihydroxy-5α-androstane or 3α,16α,17β-trihydroxy-5α-androstane.
 18. The method of claim 6 wherein the compound is 3β-hydroxy-16α-fluoro-5α-androstan-17-one, 16α-fluoroandrost-5-ene-17-one, 7β-hydroxy-16α-fluoroandrost-5-ene-17-one, 7α-hydroxy-16α-fluoroandrost-5-ene-17-one, 3α-hydroxy-16α-fluoroandrost-5-ene-17-one, 3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 3α,7β,17β-trihydroxy-16α-fluoroandrost-5-ene, 3α,17β-dihydroxy-7-oxo-16α-fluoroandrost-5-ene, 7,17-dioxo-16α-fluoroandrost-5-ene or 17β-hydroxy-7-oxo-16α-fluoroandrost-5-ene.
 19. The method of claim 6 wherein the compound is 3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene, 3β,7β,17β-trihydroxy-16-oxoandrost-5-ene, 3β,7α,17β-trihydroxyandrost-5-ene, 3β,16α,17β-trihydroxyandrost-5-ene, 3β,17β-dihydroxy-7-oxoandrost-5-ene, 3β,7β,16α,17β-tetrahydroxyandrost-5-ene or 3β,7β,17β-trihydroxy-16α-bromoandrost-5-ene.
 20. The method of claim 17 wherein the compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one.
 21. The method of claim 1 wherein the compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate.
 22. The method of claim 19 wherein the compound is 3β,17β-dihydroxyandrost-5-ene.
 23. The method of claim 19 wherein the compound is 3β,7β,17β-trihydroxyandrost-5-ene.
 24. The method of claim 19 wherein the compound is 3α,17β-dihydroxy-16α-fluoroandrost-5-ene.
 25. The method of claim 17 wherein the compound is 16β-bromo-3β-hydroxy-5α-androstan-17-one.
 26. The method of claim 17 wherein the compound is 3β,16α-dihydroxy-5α-androstan-17-one or 3α,16α,17β-trihydroxy-5α-androstane.
 27. The method of claim 1 wherein the intermittent dosing protocol comprises: (a) administering the compound to the subject at least once per day for at least 2 days; (b) not administering the one or more formula 1 compounds to the subject for at least 1 day; (c) administering the one or more formula 1 compounds to the subject at least once per day for at least 2 days; and (d) optionally repeating steps (a), (b) and (c) at least once or variations of steps (a), (b) and (c) at least once.
 28. The method of claim 27 wherein step (c) comprises the same dosing period as step (a).
 29. The method of claim 28 wherein step (a) is administering the compound for about 3-24 days.
 30. The method of claim 28 wherein step (b) is not administering the compound for about 3-120 days.
 31. The method of claim 29 wherein step (b) is not administering the compound for about 3-120 days.
 32. The method of claim 29 wherein step (b) comprises not administering the compound for about 4-60 days.
 33. The method of claim 27 wherein step (b) comprises not administering the compound for about 4-60 days.
 34. The method of claim 31 wherein the compound is 16β-bromo-3β-hydroxy-5α-androstan-17-one, 16α-bromo-3β-hydroxy-5α-androstan-17-one, 3β,16α-dihydroxy-5α-androstan-17-one, 3β,16β-dihydroxy-5α-androstan-17-one, 3β,16α,17β-trihydroxy-5α-androstane, 3β,16β,17β-trihydroxy-5α-androstane, 3α,16α,17β-trihydroxy-5α-androstane, 16α-fluoro-3β-hydroxy-5α-androstan-17-one, 16α-fluoroandrost-5-ene-17-one, 7β-hydroxy-16α-fluoroandrost-5-ene-17-one, 7α-hydroxy-16α-fluoroandrost-5-ene-17-one, 3α-hydroxy-16α-fluoroandrost-5-ene-17-one, 3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 3α,7β,17β-trihydroxy-16α-fluoroandrost-5-ene, 3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene, 3β,7α,17β-trihydroxyandrost-5-ene, 3β,16α,17β-trihydroxyandrost-5-ene, 3β,17β-dihydroxy-7-oxoandrost-5-ene, 3β,7β,16α,17β-tetrahydroxyandrost-5-ene or 3β,7β,17β-trihydroxy-16α-bromoandrost-5-ene.
 35. The method of claim 31 wherein the compound is 16β-bromo-3β-hydroxy-5α-androstan-17-one, 16α-bromo-3β-hydroxy-5α-androstan-17-one, 3β,16α-dihydroxy-5α-androstan-17-one, 3β,16β-dihydroxy-5α-androstan-17-one, 3β,16α,17β-trihydroxy-5α-androstane, 3β,16β,17β-trihydroxy-5α-androstane or 16α-fluoro-3β-hydroxy-5α-androstan-17-one.
 36. The method of claim 31 wherein the compound is 3β,17β-dihydroxyandrost-5-ene,3β,7β,17β-trihydroxyandrost-5-ene, 3β,7α,17β-trihydroxyandrost-5-ene, 3β,16α,17β-trihydroxyandrost-5-ene, 3β,17β-dihydroxy-7-oxoandrost-5-ene, 3β,7β,16α,17β-tetrahydroxyandrost-5-ene or 3β,7β,17β-trihydroxy-16α-bromoandrost-5-ene.
 37. The method of claim 35 wherein the compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one.
 38. The method of claim 37 wherein the 16α-bromo-3β-hydroxy-5α-androstan-17-one comprises 16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate.
 39. The method of claim 36 wherein the compound is 3β,7β,17β-dihydroxyandrost-5-ene.
 40. The method of claim 36 wherein the compound is 3β,7β,1762-trihydroxyandrost-5-ene.
 41. The method of claim 34 wherein the compound is 3α,17β-dihydroxy-16α-fluoroandrost-5-ene.
 42. The method of claim 35 wherein the compound is 16β-bromo-3β-hydroxy-5α-androstan-17-one.
 43. The method of claim 35 wherein the compound is 3β,16α-dihydroxy-5α-androstan-17-one.
 44. The method of claim 34, wherein the subject has a pathogen infection.
 45. The method of claim 44, wherein the pathogen infection is a viral infection.
 46. The method of claim 45, wherein the viral infection is a retrovirus infection, optionally selected from the group consisting of a HIV-1 infection and a HIV-2 infection.
 47. The method of claim 45 where the infection is a hepatitis B virus infection, a hepatitis C virus infection, a poxvirus infection or a papillomavirus infection.
 48. The method of claim 44, wherein the pathogen infection is a parasite infection.
 49. The method of claim 48, wherein the parasite infection is a Plasmodium infection, a Trypanosoma infection, a Leishmania infection, a Schistosoma infection or a Cryptosporidium infection.
 50. The method of claim 44, wherein the pathogen infection is a bacterial, fungal or yeast infection.
 51. The method of claim 50, wherein the bacterial, fungal or yeast infection is an intracellular bacterium infection, a Mycobacterium infection, a Brucella infection, a Pseudomonas infection, a Yersinia infection, a Vibrio infection, a Salmonella infection, a Candida infection, an Aspergillus infection or a Cryptococcus infection.
 52. The method of claim 34 wherein the subject has a cancer or a precancer.
 53. The method of claim 52 wherein the cancer or precancer is a cancer or precancer arising in the throat, esophagus, stomach, intestine, colon, lung, or central nervous system.
 54. The method of claim 34, wherein the subject has, or is subject to developing, an immunosuppression condition or an unwanted immune response either or both of which are associated with a chemotherapy, or radiation exposure.
 55. The method of claim 54, wherein the chemotherapy or radiation exposure is a cyclosporin, cyclohexamide, mitomycin C, adriamycin, taxol, amphotericin B, cis-platin, a protease inhibitor, a nucleoside analog, a nucleotide analog or a corticosteroid treatment or γ-radiation therapy.
 56. The method of claim 34, wherein the subject has a wound, osteoporosis, a bone fracture, a hemorrhage or a burn.
 57. The method of claim 34, wherein the subject has a neurological disorder.
 58. The method of claim 57, wherein the neurological disorder is AIDS associated dementia, Alzheimer's disease, Parkinson's disease, schizophrenia or multiple sclerosis.
 59. A method to administer a compound to a subject, wherein the method comprises intermittent administration of about 0.05 mg/kg to about 30 mg/kg per day of a compound to the subject, wherein the compound is 16β-bromo-3β-hydroxy-5α-androstan-17-one, 16α-bromo-3β-hydroxy-5α-androstan-17-one, 3β,16α-dihydroxy-5α-androstan-17-one, 3β,16β-dihydroxy-5α-androstan-17-one, 3β,16α,17β-trihydroxy-5α-androstane, 3β,16β,17β-trihydroxy-5α-androstane, 16α-fluoro-3β-hydroxy-5α-androstan-17-one, 16α-fluoroandrost-5-ene-17-one, 7β-hydroxy-16α-fluoroandrost-5-ene-17-one, 7α-hydroxy-16α-fluoroandrost-5-ene-17-one, 3α-hydroxy-16α-fluoroandrost-5-ene-17-one, 3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 3α,7β,17β-trihydroxy-16α-fluoroandrost-5-ene, 3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene, 3β,7α,17β-trihydroxyandrost-5-ene, 3β,16α,17β-trihydroxyandrost-5-ene, 3β,17β-dihydroxy-7-oxoandrost-5-ene, 3β,7β,16β,17β-tetrahydroxyandrost-5-ene or 3β,7β,17β-trihydroxy-16α-bromoandrost-5-ene.
 60. The method of claim 59 wherein the subject is a human.
 61. The method of claim 59 wherein the intermittent dosing protocol comprises the steps of: (a) administering the compound(s) to the subject at least once per day for at least 2 days; (b) not administering the compound(s) to the subject for at least 1 day; (c) administering the compound(s) to the subject at least once per day for at least 2 days; and (d) optionally repeating steps (a), (b) and (c) at least once or variations of steps (a), (b) and (c) at least once, and wherein the subject is a human.
 62. The method of claim 61 wherein step (c) comprises the same dosing regimen as step (a).
 63. The method of claim 61 wherein step (a) is administering the compound for about 3-24 days.
 64. The method of claim 62 wherein step (a) is administering the compound for about 3-24 days.
 65. The method of claim 62 wherein step (b) is not administering the compound for about 3-120 days.
 66. The method of claim 63 wherein step (b) is not administering the compound for about 3-120 days.
 67. The method of claim 62 wherein step (b) comprises not administering the compound for about 4-60 days.
 68. The method of claim 63 wherein step (b) comprises not administering the compound for about 4-60 days.
 69. The method of claim 61 wherein the compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one.
 70. The method of claim 69 wherein the 16α-bromo-3β-hydroxy-5α-androstan-17-one comprises 16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate.
 71. The method of claim 66 wherein the compound is 16α-bromo-3β-hydroxy-5α-androstan-1 7-one.
 72. The method of claim 71 wherein the 16α-bromo-3β-hydroxy-5α-androstan-17-one comprises 16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate.
 73. The method of claim 61 wherein the compound is 3β,16α-dihydroxy-5α-androstan-17-one.
 74. The method of claim 61 wherein the compound is 16β-bromo-3β-hydroxy-5α-androstan-17-one.
 75. The method of claim 61 wherein the compound is 3β,17β-dihydroxyandrost-5-ene.
 76. The method of claim 61 wherein the compound is 3β,7β,17β-trihydroxyandrost-5-ene.
 77. The method of claim 58 wherein the compound is 3α,17β-dihydroxy-16α-fluoroandrost-5-ene.
 78. A method to treat a subject having, or subject to developing, diabetes, hyperglycemia or a hyperlipidemia, comprising administering to the subject an effective amount of a compound having the structure

wherein R¹ is —OH, ═O, —OR^(PR), —SH, —SR^(PR), —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R² is —H, —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R³ is —OH, OR^(PR), —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R⁴ is —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, ═CH(CH₂)₀₋₁₅CH₃, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or R³ and both R⁴ together comprise a structure of formula 2

R⁵ and R⁶ independently are —H, —OH, —OR^(PR), —SH, —SR^(PR), —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R⁷ is —CHR¹⁰, —CHR¹⁰—CHR¹⁰—, —CHR¹⁰—CHR¹⁰—CHR¹⁰—, —CHR¹⁰—O—CHR¹⁰—, —CHR¹⁰—S—CHR¹⁰—, —CHR¹⁰—NR^(PR)—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, wherein R¹⁰ independently are —H, —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R⁸ is —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, or R⁸ is absent, leaving a 5-membered ring, wherein R¹⁰ independently are —H, —OH, —OR^(PR), ═O, —SH, —SR^(PR), S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R⁹ is —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, or R⁹ is absent, leaving a 5-membered ring, wherein R¹⁰ independently are —H, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, a thioester, an amide, an amino acid, a peptide, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are optionally independently substituted with —O—, —S— or —NR^(PR)— or where 1, 2 or 3 hydrogen atoms of the heterocycle or 1 or 2 hydrogen atoms of the 4-, 5-, 6- or 7-membered ring are substituted with —OR^(PR), —SR^(PR), N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or, one more of the ring carbons are substituted with ═0 or ═S, or D comprises two 5- or 6-membered rings, wherein the rings are fused or are linked by 1 or 2 bonds; R^(PR) is a protecting group; R¹³ independently are C1-C6 alkyl.
 79. The method of claim 78 wherein the compound is 3α,17β-dihydroxy- 16α-fluoroandrost-5-ene, 3α-hydroxy-16α-fluoroandrost-5-ene-17-one, 3α,17β-dihydroxy-16α-fluoroandrost-4-ene or 3α-hydroxy-16α-fluoroandrost-4-ene-17-one.
 80. The method of claim 78 wherein the level or activity of PPARα, LXRα or SF-1 is modulated in the subject.
 81. The method of claim 78 wherein the hyperlipidemia is hypercholesterolemia.
 82. A method to treat a subject having, or subject to developing, diabetes, hyperglycemia or a hyperlipidemia, comprising administering to the subject an effective amount of a compound having the structure

wherein R² is —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(RPR)₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R³ is —OH, —OR^(PR), —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R⁴ is —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, ═CH(CH₂)₀₋₁₅CH₃, —N₃, —NH₂, —N(RPR)₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or R³ and both R⁴ together comprise a structure of formula 2

R⁵ and R⁶ independently are —H, —OH, —OR^(PR), —SH, —SR^(PR), —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —CH₃, —NO₂, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or, R is —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —CHR¹⁰—CHR¹⁰—CHR¹⁰—, —CHR¹⁰—O—CHR¹⁰—, —CHR¹⁰—S—CHR¹⁰—, —CHR¹⁰—NR^(PR)—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, wherein R¹⁰ independently are —H, —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R⁸ is —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, or R⁹ is absent, leaving a 5-membered ring, wherein R¹⁰ independently are —H, —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R⁹ is —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, or R⁹ is absent, leaving a 5-membered ring, wherein R¹⁰ independently are —H, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, a thioester, an amide, an amino acid, a peptide, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are optionally independently substituted with —O—, —S— or —NR^(PR)— or where 1, 2 or 3 hydrogen atoms of the heterocycle or 1 or 2 hydrogen atoms of the 4-, 5-, 6- or 7-membered ring are substituted with —OR^(PR), —SR^(PR), —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or, one more of the ring carbons are substituted with ═O or ═S, or D comprises two 5- or 6-membered rings, wherein the rings are fused or are linked by 1 or 2 bonds, provided that the compound is not 3β-hydroxyandrost-5-ene-17-one, 3β-hydroxyandrost-5-ene-1 7-one 3-sulfate or an ester or ether derivative of either compound; R^(PR) is a protecting group; R¹³ independently are C1-C6 alkyl.
 83. The method of claim 82 wherein the compound is 7α,17β-dihydroxy-16α-fluoroandrost-5-ene, 7α-hydroxy-16α-fluoroandrost-5-ene-17-one, 7β,17β-dihydroxy-16α-fluoroandrost-4-ene or 7β-hydroxy-16α-fluoroandrost-4-ene-17-one.
 84. The method of claim 82 wherein the level or activity of PPARα, LXRα or SF-1 is modulated in the subject.
 85. The method of claim 82 wherein the hyperlipidemia is hypercholesterolemia.
 86. A method to treat or prevent an infection in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a formulation comprising (1) one or more excipients and (2) a compound(s) selected from the group consisting of (i) 16α-bromo-3β-hydroxy-5α-androstan-17-one, (ii) 16β-bromo-3β-hydroxy-5α-androstan-17-one, (iii) 16α-bromo-3β-hydroxy-5α-androstan-17-one and 16β-bromo-3β-hydroxy-5α-androstan-17-one and (iv) 3β,16α-dihydroxy-5α-androstan-17-one, and wherein the infection is selected from the group consisting of a Plasmodium infection, a Trypanosoma infection, a togavirus infection, a flavivirus infection, a hepadnavirus infection, a papillomavirus infection, a Candida infection, a Mycoplasma infection, a Cryptosporidium infection or a Toxoplasma infection.
 87. The method of claim 86 wherein the pathogen infection is a togavirus infection, a flavivirus infection or a hepadnavirus infection.
 88. The method of claim 87 wherein the togavirus infection, flavivirus infection or hepadnavirus infection is a hepatitis C virus infection or a hepatitis B virus infection.
 89. The method of claim 29 wherein the pathogen infection is a Plasmodium infection.
 90. A liquid formulation that contains less than about 3% v/v water and comprises (1) 16α-bromo-3β-hydroxy-5α-androstan-17-one and/or 16β-bromo-3β-hydroxy-5α-androstan-17-one and (2) liquid excipients selected from the group consisting of (i) propylene glycol, a polyethylene glycol and ethanol, (ii) propylene glycol, a polyethylene glycol and benzyl alcohol, (iii) propylene glycol and a polyethylene glycol and (iv) propylene glycol, a polyethylene glycol and benzyl benzoate.
 91. The formulation of claim 90 wherein the formulation comprises less than about 0.3% v/v water.
 92. The formulation of claim 90 wherein the formulation contains about 0.5-100 mg/mL of 16α-bromo-3β-hydroxy-5α-androstan-17-one.
 93. The formulation of claim 92 wherein the formulation comprises less than about 0.3% v/v water.
 94. The formulation of claim 89 wherein the formulation further comprises a local anaesthetic.
 95. A product produced by the process of contacting a composition comprising 16α-bromo-3β-hydroxy-5α-androstan-17-one and/or 16β-bromo-3β-hydroxy-5α-androstan-17-one and two liquid excipients with a third liquid excipient wherein the product comprises less than about 3% v/v water.
 96. The product of claim 95 wherein the product comprises less than about 0.3% v/v water.
 97. The product of claim 95 wherein the two liquid excipients are selected from a polyethylene glycol, propylene glycol, benzyl benzoate and an alcohol selected from the group consisting of benzyl alcohol and ethanol.
 98. The product of claim 95 wherein the third liquid excipient is a polyethylene glycol, propylene glycol, benzyl benzoate or ethanol.
 99. A product produced by the process of contacting a composition comprising 16α-bromo-3β-hydroxy-5α-androstan-17-one or 16β-bromo-3β-hydroxy-5α-androstan-17-one and three liquid excipients with a fourth liquid excipient wherein the product comprises less than about 3% v/v water.
 100. The product of claim 99 wherein the product comprises less than about 0.3% v/v water.
 101. The product of claim 99 wherein the three liquid excipients are selected from a polyethylene glycol, propylene glycol, benzyl benzoate and an alcohol selected from the group consisting of benzyl alcohol and ethanol.
 102. The product of claim 101 wherein the fourth liquid excipient is a polyethylene glycol, propylene glycol, benzyl benzoate, benzyl alcohol or ethanol.
 103. The product of claim 95 wherein the product has been stored in a closed container at about 5-40° C. for about 30 minutes to about 2 years.
 104. The product of claim 99 wherein the product has been stored in a closed container at about 5-40° C. for about 30 minutes to about 2 years.
 105. A compound having the structure

wherein the dotted lines are optional double bonds; R¹ is —H; R² is —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R³ is —OH, —OR^(PR), —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R⁴ independently are —H, —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, ═CH(CH₂)₀₋₁₅CH₃, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, provided that both R⁴ are not —H, or R³ and both R⁴ together comprise a structure of formula 2

R⁵ and R⁶ independently are —H, —OH, —OR^(PR), —SH, —SR^(PR), —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —CH₃, —NO₂, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or, R⁷ is —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —CHR¹⁰—CHR¹⁰—CHR¹⁰—, —CHR¹⁰—O—CHR¹⁰—, —CHR¹⁰—S—CHR¹⁰—, —CHR¹⁰—NR^(PR)—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, wherein R¹⁰ independently are —H, —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R⁸ is —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, NR^(PR)— or —NR^(PR)—CHR¹⁰—, or R⁸ is absent, leaving a 5-membered ring, wherein R¹⁰ independently are —H, —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R⁹ is —CHR¹⁰—, —CHR¹⁰—CHR , —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, or R⁹ is absent, leaving a 5-membered ring, wherein R¹⁰ independently are —H, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, a thioester, an amide, an amino acid, a peptide, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R¹⁰ independently are —OH, —OR^(PR), ═O, —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are optionally independently substituted with —O—, —S— or —NR^(PR)— or where 1, 2 or 3 hydrogen atoms of the heterocycle or 1 or 2 hydrogen atoms of the 4-, 5-, 6- or 7-membered ring are substituted with —OR^(PR), —SR^(PR), N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or, one more of the ring carbons are substituted with ═O or ═S, or D comprises two 5- or 6-membered rings, wherein the rings are fused or are linked by 1 or 2 bonds, provided that the compound is not 3β-hydroxyandrost-5-ene-17-one, 3β-hydroxyandrost-5-ene-1 7-one 3-sulfate or an ester or ether derivative of either compound; R^(PR) is a protecting group; R¹³ independently are C1-C6 alkyl.
 106. The compound of claim 105 having the structure


107. The compound of claim 105 wherein the compound is 7β-hydroxy-16α-fluoroandrost-5-ene-17-one, 7α-hydroxy-16α-fluoroandrost-5-ene-17-one, 16α-fluoroandrost-5-ene-7,17-dione, 7β,17β-dihydroxy-16α-fluoroandrost-5-ene or 7α,17β-dihydroxy-16α-fluoroandrost-5-ene.
 108. A formulation comprising one or more excipients and a compound of claim
 105. 108. A formulation comprising one or more excipients and a compound of claim
 106. 109. A formulation comprising one or more excipients and a compound of claim
 107. 110. The method of claim 34 wherein the condition is an allergy or inflammation condition.
 111. The method of claim 110, wherein the allergy or inflammation condition is allergic bronchopulmonary aspergillosis, atopic asthma, allergic respiratory disease, allergic rhinitis, atopic dermatitis, lung fibrosis, subepithelial fibrosis in airway hyperresponsiveness, chronic sinusitis, perennial allergic rhinitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, chronic diarrhea or fibrosing alveolitis.
 110. The method of claim 34, wherein the condition is an autoimmune disease.
 111. The method of claim 27, wherein the autoimmune disease is systemic lupus erythematosus, myasthenia gravis, Grave's disease, diabetes, rheumatoid arthritis or osteoarthritis.
 112. A compound having the structure

wherein, the dotted lines are optional double bonds; R¹ and R² independently are —OH, —OR^(PR), —SH, —SR^(PR), —O—Si—(R¹³)₃, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an ether, a thioether, a carbonate, a carbamate, an optionally substituted monosaccharide or an optionally substituted oligosaccharide; R³ is —OH, —OR^(PR), —SH, —SR^(PR), —O—Si—(R¹³)₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an ether, a thioether, a carbonate, a carbamate, an optionally substituted monosaccharide or an optionally substituted oligosaccharide; each R⁴ independently is —OH, —OR^(PR), —SH, —SR^(PR), —O—Si—(R¹³)₃, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an ether, a thioether, a carbonate, a carbamate, an optionally substituted monosaccharide or an optionally substituted oligosaccharide, provided that both R⁴ are not —H; R⁵ and R independently are —H, —OH, —OR^(PR), —SH, —SR^(PR), —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R is —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —CHR¹⁰—CHR¹⁰—CHR¹⁰—, —CHR¹⁰—O—CHR¹⁰—, —CHR¹⁰—S—CHR¹⁰—, —CHR¹⁰—NR^(PR)—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—; R⁸ and R⁹ independently are —CHR¹⁰—, —CHR¹⁰—CHR¹⁰—, —O—, —O—CHR¹⁰—, —S—, —S—CHR¹⁰—, —NR^(PR)— or —NR^(PR)—CHR¹⁰—, or R⁸ or R⁹ independently is absent, leaving a 5-membered ring; R¹⁰ independently are —H, —OH, ═O, —OR^(PR), —SH, —SR^(PR), ═S, ═CH₂, —N₃, —NH₂, —N(R^(PR))₂, —O—Si—(R¹³)₃, —CN, —NO₂, ═NOH, ═NOC(O)CH₃, —C(O)—CH₃, —F, —Cl, —Br, —I, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a thioacetal, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer; R¹³ independently are C₁₆ alkyl; and R^(PR) independently are a protecting group.
 113. A formulation comprising a compound of claim 105 and one or more excipients.
 114. The formulation of claim 113 wherein the formulation is for buccal or sublingual administration to a human.
 115. The formulation of claim 113 wherein the formulation is for parenteral or topical administration to a human.
 116. A formulation comprising a compound of claim 112 and one or more excipients.
 117. The formulation of claim 116 wherein the formulation is for buccal or sublingual administration to a human.
 118. The formulation of claim 116 wherein the formulation is for parenteral or topical administration to a human.
 119. The compound of claim 112 having the structure

wherein, R⁴ is —OH, —OR^(PR), —SH, —SR^(PR), —O—Si—(R¹³)₃, an ester, a thioester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an ether, a thioether, a carbonate, a carbamate, an optionally substituted monosaccharide or an optionally substituted oligosaccharide.
 120. The compound of claim 119 wherein R¹, R², R³ and R⁴ are —OH.
 121. The compound of claim 119 wherein R¹, R² and R⁴ are —OH and R³ is —F, —Cl, —Br or —I.
 122. A formulation comprising a compound of claim 119 and one or more excipients.
 123. The formulation of claim 122 wherein the formulation is for buccal or sublingual administration to a human.
 124. The formulation of claim 122 wherein the formulation is for parenteral or topical administration to a human. 